2024-03-28T20:50:20Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/3218042019-08-30T11:36:33Zcom_10033_620601col_10033_620603
2014-06-18T09:56:01Z
urn:hdl:10033/321804
Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells.
Pessler, Frank
Ogdie, Alexis R
Mayer, Christian T
Kretzschmar, Warren W
Dai, Lie
Elsaman, Ahmed M
Einhorn, Eugene
Krenn, Veit
Schumacher, H Ralph
To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM).
2014-06-18T09:56:01Z
2014-06-18T09:56:01Z
2014-03
Article
Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells. 2014, 21 (1):28-34 Amyloid
1744-2818
24286442
10.3109/13506129.2013.862229
http://hdl.handle.net/10033/321804
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
en
Archived with thanks to Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
oai:repository.helmholtz-hzi.de:10033/6209552019-08-30T11:24:31Zcom_10033_620601col_10033_620603
2017-06-16T08:07:40Z
urn:hdl:10033/620955
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature
Möller, Jana C
Cron, Randy Q
Young, Daniel W
Girschick, Hermann J
Levy, Deborah M
Sherry, David D
Kukita, Akiko
Saijo, Kaoru
Pessler, Frank
Abstract Spinal epidural lipomatosis is a rare complication of chronic corticosteroid treatment. We report a new pediatric case and an analysis of this and 19 pediatric cases identified in the international literature. The youngest of these combined 20 patients was 5 years old when lipomatosis was diagnosed. Lipomatosis manifested after a mean of 1.3 (+/- 1.5) years (SD) (median, 0.8 years; range, 3 weeks - 6.5 years) of corticosteroid treatment. The corticosteroid dose at the time of presentation of the lipomatosis ranged widely, between 5 and 80 mg of prednisone/day. Back pain was the most common presenting symptom. Imaging revealed that lipomatosis almost always involved the thoracic spine, extending into the lumbosacral region in a subset of patients. Predominantly lumbosacral involvement was documented in only two cases. Although a neurological deficit at presentation was documented in about half of the cases, surgical decompression was not performed in the cases reported after 1996. Instead, reducing the corticosteroid dose (sometimes combined with dietary restriction to mobilize fat) sufficed to induce remission. In summary, pediatric spinal epidural lipomatosis remains a potentially serious untoward effect of corticosteroid treatment, which, if recognized in a timely manner, can have a good outcome with conservative treatment.
2017-06-16T08:07:40Z
2017-06-16T08:07:40Z
2011-02-01
2015-09-04T08:24:15Z
Journal Article
Pediatric Rheumatology. 2011 Feb 01;9(1):5
http://dx.doi.org/10.1186/1546-0096-9-5
http://hdl.handle.net/10033/620955
en
Möller et al; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/6207152019-08-30T11:26:42Zcom_10033_620601col_10033_620603
2017-01-17T09:49:01Z
urn:hdl:10033/620715
Analysis of contingency tables based on generalised median polish with power transformations and non-additive models
Klawonn, Frank
Jayaram, Balasubramaniam
Crull, Katja
Kukita, Akiko
Pessler, Frank
Abstract Contingency tables are a very common basis for the investigation of effects of different treatments or influences on a disease or the health state of patients. Many journals put a strong emphasis on p-values to support the validity of results. Therefore, even small contingency tables are analysed by techniques like t-test or ANOVA. Both these concepts are based on normality assumptions for the underlying data. For larger data sets, this assumption is not so critical, since the underlying statistics are based on sums of (independent) random variables which can be assumed to follow approximately a normal distribution, at least for a larger number of summands. But for smaller data sets, the normality assumption can often not be justified. Robust methods like the Wilcoxon-Mann-Whitney-U test or the Kruskal-Wallis test do not lead to statistically significant p-values for small samples. Median polish is a robust alternative to analyse contingency tables providing much more insight than just a p-value. Median polish is a technique that provides more information than just a p-value. It explains the contingency table in terms of an overall effect, row and columns effects and residuals. The underlying model for median polish is an additive model which is sometimes too restrictive. In this paper, we propose two related approach to generalise median polish. A power transformation can be applied to the values in the table, so that better results for median polish can be achieved. We propose a graphical method how to find a suitable power transformation. If the original data should be preserved, one can apply other transformations – based on so-called additive generators – that have an inverse transformation. In this way, median polish can be applied to the original data, but based on a non-additive model. The non-linearity of such a model can also be visualised to better understand the joint effects of rows and columns in a contingency table.
2017-01-17T09:49:01Z
2017-01-17T09:49:01Z
2013-05-30
2015-09-04T08:29:46Z
Journal Article
Health Information Science and Systems. 2013 May 30;1(1):11
http://dx.doi.org/10.1186/2047-2501-1-11
http://hdl.handle.net/10033/620715
en
Klawonn et al.; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/6207052019-08-30T11:25:43Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
2017-01-16T15:28:50Z
urn:hdl:10033/620705
Infection- and procedure-dependent effects on pulmonary gene expression in the early phase of influenza A virus infection in mice
Preusse, Matthias
Tantawy, Mohamed A
Klawonn, Frank
Schughart, Klaus
Pessler, Frank
Abstract Background Investigating the host response in the early stage of influenza A virus (IAV) infection is of considerable interest. However, it is conceivable that effects due to the anesthesia and/or intranasal infection procedure might introduce artifacts. We therefore aimed to evaluate the effects of anesthesia and/or intranasal infection on transcription of selected pulmonary mRNAs in two inbred mouse strains with differential susceptibility to IAV infection. Results DBA/2J and C57BL/6J mice were evaluated in a time course experiment in which lung tissue was sampled after 6, 12, 18, 24, 48 and 120 h. After anesthesia with ketamine and xylazine, a suspension of mouse-adapted IAV strain PR8_Mun in 20 μl sterile buffer, or 20 μl sterile buffer only, was instilled intranasally. The mice receiving anesthesia and PBS only were designated the “mock treatment” group. Pulmonary expression of 10 host mRNAs (Fos, Retnla, Irg1, Il6, Il1b, Cxcl10, Stat1, Ifng, Ifnl2, and Mx1) and viral hemagglutinin (HA) mRNA were determined at the designated time points. As expected, weight loss and viral replication were greater in the DBA/2J strain (which is more susceptible to IAV infection). Four mRNAs (Retnla, Irg1, Il6, and Cxcl10) were procedure-dependently regulated in DBA/2J mice between 6 and 24 h, and two (Retnla and Il6) in C57BL/6J mice, although to a lesser extent. All 10 mRNAs rose after infection, but one (Fos) only in DBA/2J mice. These infection-dependent effects could be separated from procedure-dependent effects beginning around 12 h in DBA/2J and 18 h in C57BL/6J mice. The interferon-related mRNAs Stat1, Ifng, Infl2, and Mx1 were unaffected by mock treatment in either mouse strain. Mx1 and Infl2 correlated best with HA mRNA expression (r = 0.97 and 0.93, respectively, in DBA/2J). Conclusions These results demonstrate effects of the anesthesia and/or intranasal infection procedure on pulmonary gene expression, which are detectable between approximately 6 and 24 h post procedure and vary in intensity and temporal evolution depending on the mouse strain used. Mock infection controls should be included in all studies on pulmonary gene expression in the early phase of infection with IAV and, likely, other respiratory pathogens.
2017-01-16T15:28:50Z
2017-01-16T15:28:50Z
2013-12-17
2015-09-04T08:30:14Z
Journal Article
BMC Microbiology. 2013 Dec 17;13(1):293
http://dx.doi.org/10.1186/1471-2180-13-293
http://hdl.handle.net/10033/620705
en
Preusse et al.; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/5801112019-08-30T11:35:14Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
2015-10-22T08:39:41Z
urn:hdl:10033/580111
Improved coverage and timing of childhood vaccinations in two post-Soviet countries, Armenia and Kyrgyzstan.
Schweitzer, A
Krause, Gerard
Pessler, F
Akmatov, M K
Timing of childhood vaccinations has received close attention in many countries. Little is known about the trends in correctly timed vaccination in former Soviet countries. We examined trends in vaccination coverage and correct timing of vaccination in two post-Soviet countries, Armenia and Kyrgyzstan, and analyzed factors associated with delayed vaccinations.
2015-10-22T08:39:41Z
2015-10-22T08:39:41Z
2015
Article
Improved coverage and timing of childhood vaccinations in two post-Soviet countries, Armenia and Kyrgyzstan. 2015, 15 (1):798 BMC Public Health
1471-2458
26285702
10.1186/s12889-015-2091-9
http://hdl.handle.net/10033/580111
BMC public health
en
oai:repository.helmholtz-hzi.de:10033/5800702019-08-30T11:36:33Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
2015-10-22T10:22:07Z
urn:hdl:10033/580070
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains.
Preusse, Matthias
Schughart, Klaus
Wilk, Esther
Klawonn, Frank
Pessler, Frank
Helmholz Centre for Infection Research
Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters.
2015-10-22T10:22:07Z
2015-10-22T10:22:07Z
2015
Article
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains. 2015, 8:225 BMC Res Notes
1756-0500
26047817
10.1186/s13104-015-1195-8
http://hdl.handle.net/10033/580070
BMC research notes
en
oai:repository.helmholtz-hzi.de:10033/5944072019-08-30T11:37:44Zcom_10033_620601col_10033_620603
2016-01-20T14:24:12Z
urn:hdl:10033/594407
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature.
Möller, Jana C
Cron, Randy Q
Young, Daniel W
Girschick, Hermann J
Levy, Deborah M
Sherry, David D
Kukita, Akiko
Saijo, Kaoru
Pessler, Frank
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Spinal epidural lipomatosis is a rare complication of chronic corticosteroid treatment. We report a new pediatric case and an analysis of this and 19 pediatric cases identified in the international literature. The youngest of these combined 20 patients was 5 years old when lipomatosis was diagnosed. Lipomatosis manifested after a mean of 1.3 (+/- 1.5) years (SD) (median, 0.8 years; range, 3 weeks - 6.5 years) of corticosteroid treatment. The corticosteroid dose at the time of presentation of the lipomatosis ranged widely, between 5 and 80 mg of prednisone/day. Back pain was the most common presenting symptom. Imaging revealed that lipomatosis almost always involved the thoracic spine, extending into the lumbosacral region in a subset of patients. Predominantly lumbosacral involvement was documented in only two cases. Although a neurological deficit at presentation was documented in about half of the cases, surgical decompression was not performed in the cases reported after 1996. Instead, reducing the corticosteroid dose (sometimes combined with dietary restriction to mobilize fat) sufficed to induce remission. In summary, pediatric spinal epidural lipomatosis remains a potentially serious untoward effect of corticosteroid treatment, which, if recognized in a timely manner, can have a good outcome with conservative treatment.
2016-01-20T14:24:12Z
2016-01-20T14:24:12Z
2011
Article
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature. 2011, 9 (1):5 Pediatr Rheumatol Online J
1546-0096
21284882
10.1186/1546-0096-9-5
http://hdl.handle.net/10033/594407
Pediatric rheumatology online journal
en
oai:repository.helmholtz-hzi.de:10033/6106862019-08-30T11:30:58Zcom_10033_620601col_10033_620603
2016-05-25T13:35:19Z
urn:hdl:10033/610686
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages.
Tallam, Aravind
Perumal, Thaneer M
Antony, Paul M
Jäger, Christian
Fritz, Joëlle V
Vallar, Laurent
Balling, Rudi
Del Sol, Antonio
Michelucci, Alessandro
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. To this end, we studied IRG1 expression in human immune cells under different inflammatory stimuli, such as TNFα and IFNγ, in addition to lipopolysaccharides. Under these conditions, as previously shown in mouse macrophages, IRG1/CAD accumulates in mitochondria. Furthermore, using literature information and transcription factor prediction models, we re-constructed raw gene regulatory networks (GRNs) for IRG1 in mouse and human macrophages. We further implemented a contextualization algorithm that relies on genome-wide gene expression data to infer putative cell type-specific gene regulatory interactions in mouse and human macrophages, which allowed us to predict potential transcriptional regulators of IRG1. Among the computationally identified regulators, siRNA-mediated gene silencing of interferon regulatory factor 1 (IRF1) in macrophages significantly decreased the expression of IRG1/CAD at the gene and protein level, which correlated with a reduced production of itaconic acid. Using a synergistic approach of both computational and experimental methods, we here shed more light on the transcriptional machinery of IRG1 expression and could pave the way to therapeutic approaches targeting itaconic acid levels.
2016-05-25T13:35:19Z
2016-05-25T13:35:19Z
2016
Article
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages. 2016, 11 (2):e0149050 PLoS ONE
1932-6203
26872335
10.1371/journal.pone.0149050
http://hdl.handle.net/10033/610686
PloS one
en
oai:repository.helmholtz-hzi.de:10033/6119822019-08-30T11:30:32Zcom_10033_620601col_10033_620603
2016-06-07T13:09:29Z
urn:hdl:10033/611982
Small Non-coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications.
Samir, Mohamed
Pessler, Frank
Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
MicroRNAs (miRNAs) represent a class of small non-coding RNA (sncRNA) molecules that can regulate mRNAs by inducing their degradation or by blocking translation. Considering that miRNAs are ubiquitous, stable, and conserved across animal species, it seems feasible to exploit them for clinical applications. Unlike in human viral diseases, where some miRNA-based molecules have progressed to clinical application, in veterinary medicine, this concept is just starting to come into view. Clinically, miRNAs could represent powerful diagnostic tools to pinpoint animal viral diseases and/or prognostic tools to follow up disease progression or remission. Additionally, the possible consequences of miRNA dysregulation make them potential therapeutic targets and open the possibilities to use them as tools to generate viral disease-resistant livestock. This review presents an update of preclinical studies on using sncRNAs to combat viral diseases that affect pet and farm animals. Moreover, we discuss the possibilities and challenges of bringing these bench-based discoveries to the veterinary clinic.
2016-06-07T13:09:29Z
2016-06-07T13:09:29Z
2016
Article
Small Non-coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications. 2016, 3:22 Front Vet Sci
2297-1769
27092305
10.3389/fvets.2016.00022
http://hdl.handle.net/10033/611982
Frontiers in veterinary science
en
oai:repository.helmholtz-hzi.de:10033/6190432019-08-30T11:30:58Zcom_10033_620601col_10033_620603
2016-08-30T11:19:08Z
urn:hdl:10033/619043
Exhaled breath analysis in childhood rheumatic disorders--a longitudinal study.
Hendel, N
Akmatov, M K
Hamel, J
Vogelberg, C
Pessler, F
TWINCORE Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7 30625 Hannover, Germany.
We aimed to evaluate the fraction of exhaled nitric oxide (FENO50) and deaerated exhaled breath condensate pH (dEBCpH) as non-invasive markers of subclinical airway inflammation in pediatric patients with rheumatologic disorders. We determined FENO50 and dEBCpH in a prospective study spanning at least 12 months, comprising 85 pediatric patients with rheumatologic disorders, including juvenile idiopathic arthritis (JIA, n = 63), chronic recurrent multifocal osteomyelitis (CRMO, n = 6), systemic lupus erythematosus (SLE, n = 3), juvenile dermatomyositis (JDM, n = 1) and other rheumatic disorders (n = 12). dEBCpH was determined once in a group of children without evidence of rheumatologic or pulmonary disease (controls, n = 90). Findings were correlated with results of pulmonary function tests. Atopic sensitization was assessed by RAST or skin prick test in 76 patients. Atopic sensitization was detected in 34% (26/76) of patients. Neither FENO50 nor dEBCpH correlated with disease activity, but intermediately (20-35 ppb) or highly elevated (>35 ppb) levels were observed at least once in 26 patients (31%), 19 of whom had atopic sensitization. Median dEBCpH did not differ between cases and controls (8.05 versus 8.02; p = 0.48). Median dEBCpH decreased slightly over the study period (p = 0.02), whereas FENO50 values did not change significantly (p = 0.89). There were several patients with significantly abnormal dEBCpH values that could not be readily explained by diagnosis, higher disease activity, medications, or atopic sensitization. Thus, there were no consistent abnormalities in FENO50 or dEBCpH in this cohort of Caucasian patients with relatively stable rheumatologic disorders, but there were some patients with abnormal values of unknown significance.
2016-08-30T11:19:08Z
2016-08-30T11:19:08Z
2016-06
Article
Exhaled breath analysis in childhood rheumatic disorders--a longitudinal study. 2016, 10 (2):021001 J Breath Res
1752-7163
27093271
10.1088/1752-7155/10/2/021001
http://hdl.handle.net/10033/619043
Journal of breath research
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6190492019-08-30T11:30:58Zcom_10033_620601col_10033_620603
2016-08-30T15:08:52Z
urn:hdl:10033/619049
Real-life practice of methotrexate toxicity monitoring in juvenile idiopathic arthritis in Germany, Switzerland and Austria: results of a cross-sectional assessment conducted in 2012.
Akmatov, Manas K
Stumme, Melanie
Pessler, Frank
TWINCORE Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7 30625 Hannover, Germany.
Methotrexate (MTX) is used at low doses to treat rheumatologic disorders in the paediatric age group. Toxicity is observed despite the low doses used. Even though recommendations for monitoring of early signs of toxicity exist in many countries, real-life practice may vary. We therefore assessed current practice in Germany, Switzerland and Austria.
2016-08-30T15:08:52Z
2016-08-30T15:08:52Z
2016-08-30
Article
Real-life practice of methotrexate toxicity monitoring in juvenile idiopathic arthritis in Germany, Switzerland and Austria: results of a cross-sectional assessment conducted in 2012., 34 (3):548-53 Clin. Exp. Rheumatol.
0392-856X
27156925
http://hdl.handle.net/10033/619049
Clinical and experimental rheumatology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6192652019-08-30T11:30:32Zcom_10033_620601col_10033_620603
2016-09-02T09:22:12Z
urn:hdl:10033/619265
Impact of rotavirus vaccination on coverage and timing of pentavalent vaccination - Experience from 2 Latin American countries.
Schweitzer, A
Pessler, F.
Akmatov, M K
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
We examined the coverage and timing of rotavirus vaccination and the impact of rotavirus vaccine introduction on coverage and timing of the pentavalent vaccine. We used data from the Demographic and Health Surveys in Honduras (2011/2012) and Peru (2012). The samples were divided into 2 subcohorts: children born before and after the introduction of rotavirus vaccine. We compared coverage and timing of the pentavalent vaccine in the aforementioned subcohorts. Coverage with the first and second doses of rotavirus vaccination was 95% (95% confidence intervals: 93-97%) and 91% (89-95%) in Honduras and 79% (77-82%) and 72% (69-75%) in Peru, respectively. Coverage increased in both countries over the years. The proportion of children vaccinated according to age-appropriate vaccination schedules varied between 67% (second dose of rotavirus vaccinations in Peru) and 89% (first dose of rotavirus vaccination in Honduras). Coverage with the first and second doses of pentavalent vaccination remained constant over the years in Honduras, while in Peru there was a significant increase in coverage over the years (p for trend, <0.0001). In both countries, timing of pentavalent vaccination was better in post-rota-cohorts than in pre-rota-cohorts. Since its introduction, coverage of rotavirus vaccination has improved over time in both countries. An introduction of rotavirus vaccination in both countries appears to have improved the coverage and timing of other similarly scheduled vaccinations.
2016-09-02T09:22:12Z
2016-09-02T09:22:12Z
2016-05-03
Article
Impact of rotavirus vaccination on coverage and timing of pentavalent vaccination - Experience from 2 Latin American countries. 2016, 12 (5):1250-6 Hum Vaccin Immunother
2164-554X
26833132
10.1080/21645515.2015.1127486
http://hdl.handle.net/10033/619265
Human vaccines & immunotherapeutics
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6205402019-08-30T11:27:16Zcom_10033_620601col_10033_620603
2016-09-29T09:03:26Z
urn:hdl:10033/620540
Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection.
Dudek, M
Puttur, F
Arnold-Schrauf, C
Kühl, A A
Holzmann, B
Henriques-Normark, B
Berod, L
Sparwasser, T
Twincore
The Gram-positive bacterium Streptococcus pneumoniae causes life-threatening infections, especially among immunocompromised patients. The host's immune system senses S. pneumoniae via different families of pattern recognition receptors, in particular the Toll-like receptor (TLR) family that promotes immune cell activation. Yet, while single TLRs are dispensable for initiating inflammatory responses against S. pneumoniae, the central TLR adapter protein myeloid differentiation factor 88 (MyD88) is of vital importance, as MyD88-deficient mice succumb rapidly to infection. Since MyD88 is ubiquitously expressed in hematopoietic and non-hematopoietic cells, the extent to which MyD88 signaling is required in different cell types to control S. pneumoniae is unknown. Therefore, we used novel conditional knockin mice to investigate the necessity of MyD88 signaling in distinct lung-resident myeloid and epithelial cells for the initiation of a protective immune response against S. pneumoniae. Here, we show that MyD88 signaling in lysozyme M (LysM)- and CD11c-expressing myeloid cells, as well as in pulmonary epithelial cells, is critical to restore inflammatory cytokine and antimicrobial peptide production, leading to efficient neutrophil recruitment and enhanced bacterial clearance. Overall, we show a novel synergistic requirement of compartment-specific MyD88 signaling in S. pneumoniae immunity.
2016-09-29T09:03:26Z
2016-09-29T09:03:26Z
2016-09
Article
Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection. 2016, 9 (5):1288-302 Mucosal Immunol
1935-3456
26627460
10.1038/mi.2015.128
http://hdl.handle.net/10033/620540
Mucosal immunology
en
oai:repository.helmholtz-hzi.de:10033/6206792019-08-30T11:37:24Zcom_10033_620601col_10033_620603
2017-01-05T10:48:04Z
urn:hdl:10033/620679
Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood.
de Araujo, Leonardo S
Vaas, Lea A I
Ribeiro-Alves, Marcelo
Geffers, Robert
Mello, Fernanda C Q
de Almeida, Alexandre S
Moreira, Adriana da S R
Kritski, Afrânio L
Lapa E Silva, José R
Moraes, Milton O
Pessler, Frank
Saad, Maria H F
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation of DOCK9, EPHA4, and NPC2 mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil, n = 129) or reanalysis of public microarray data (UK: n = 96; South Africa: n = 51; Germany: n = 26; and UK/France: n = 63). In the Brazilian cohort, significant modulation of all target-genes was observed comparing TB vs. healthy recent close TB contacts (rCt). With a 92% specificity, NPC2 mRNA high expression (NPC2(high)) showed the highest sensitivity (85%, 95% CI 65%-96%; area under the ROC curve [AUROC] = 0.88), followed by EPHA4 (53%, 95% CI 33%-73%, AUROC = 0.73) and DOCK9 (19%, 95% CI 7%-40%; AUROC = 0.66). All the other reanalyzed cohorts corroborated the potential of NPC2(high) as a biomarker for TB (sensitivity: 82-100%; specificity: 94-97%). An NPC2(high) profile was also observed in 60% (29/48) of the tuberculin skin test positive rCt, and additional follow-up evaluation revealed changes in the expression levels of NPC2 during the different stages of Mycobacterium tuberculosis infection, suggesting that further studies are needed to evaluate modulation of this gene during latent TB and/or progression to active disease. Considering its high specificity, our data indicate, for the first time, that NPC2(high) might serve as an accurate single-gene biomarker for TB.
2017-01-05T10:48:04Z
2017-01-05T10:48:04Z
2016
Article
Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood. 2016, 7:1586 Front Microbiol
27826286
10.3389/fmicb.2016.01586
http://hdl.handle.net/10033/620679
Frontiers in microbiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208852019-08-30T11:36:04Zcom_10033_620601col_10033_620603
2017-04-04T14:01:28Z
urn:hdl:10033/620885
Seroprevalence of hepatitis B, hepatitis C, human immunodeficiency virus, Treponema pallidum, and co-infections among blood donors in Kyrgyzstan: a retrospective analysis (2013-2015).
Karabaev, Bakyt B
Beisheeva, Nurgul J
Satybaldieva, Aiganysh B
Ismailova, Aikul D
Pessler, Frank
Akmatov, Manas K
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Post-Soviet Kyrgyzstan has experienced a major surge in blood-borne infections, but data from adequately powered, up-to-date studies are lacking. We thus examined a) the seroprevalences of hepatitis B virus surface antigen (HBsAg), HIV-1 p24 antigen and antibodies against hepatitis C virus (anti-HCV), human immunodeficiency viruses (anti-HIV-1/2, HIV-1 group O), and Treponema pallidum among blood donors in Kyrgyzstan and assess their distribution according to sex, age, and provinces of residence; b) trends in the respective seroprevalences; and c) co-infection rates among the pathogens studied.
2017-04-04T14:01:28Z
2017-04-04T14:01:28Z
2017-02-21
Article
Seroprevalence of hepatitis B, hepatitis C, human immunodeficiency virus, Treponema pallidum, and co-infections among blood donors in Kyrgyzstan: a retrospective analysis (2013-2015). 2017, 6 (1):45 Infect Dis Poverty
2049-9957
28222792
10.1186/s40249-017-0255-9
http://hdl.handle.net/10033/620885
Infectious diseases of poverty
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208922019-08-30T11:29:47Zcom_10033_267632com_10033_211390com_10033_620601col_10033_267633col_10033_211409col_10033_620603
2017-04-07T10:09:11Z
urn:hdl:10033/620892
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design.
Rübsamen, Nicole
Akmatov, Manas K
Castell, Stefanie
Karch, André
Mikolajczyk, Rafael T
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice).
2017-04-07T10:09:11Z
2017-04-07T10:09:11Z
2017
Article
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design. 2017, 14:4 Emerg Themes Epidemiol
28344629
10.1186/s12982-017-0058-2
http://hdl.handle.net/10033/620892
Emerging themes in epidemiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208962019-08-30T11:29:47Zcom_10033_620601col_10033_620603
2017-04-13T13:15:22Z
urn:hdl:10033/620896
Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination.
Akmatov, Manas K
Jentsch, Leonhard
Riese, Peggy
May, Marcus
Ahmed, Malik W
Werner, Damaris
Rösel, Anja
Prokein, Jana
Bernemann, Inga
Klopp, Norman
Prochnow, Blair
Illig, Thomas
Schindler, Christoph
Guzman, Carlos A
Pessler, Frank
Twincore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Participation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly.
2017-04-13T13:15:22Z
2017-04-13T13:15:22Z
2017-02-02
Article
Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination. 2017, 17 (1):18 BMC Med Res Methodol
1471-2288
28148221
10.1186/s12874-017-0302-z
http://hdl.handle.net/10033/620896
BMC medical research methodology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209222019-08-30T11:29:47Zcom_10033_620601com_10033_620533col_10033_621891col_10033_620603
2017-05-17T12:45:45Z
urn:hdl:10033/620922
Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study - findings from Pretest 1 of the German National Cohort.
Akmatov, Manas K
Koch, Nadine
Vital, Marius
Ahrens, Wolfgang
Flesch-Janys, Dieter
Fricke, Julia
Gatzemeier, Anja
Greiser, Halina
Günther, Kathrin
Illig, Thomas
Kaaks, Rudolf
Krone, Bastian
Kühn, Andrea
Linseisen, Jakob
Meisinger, Christine
Michels, Karin
Moebus, Susanne
Nieters, Alexandra
Obi, Nadia
Schultze, Anja
Six-Merker, Julia
Pieper, Dietmar H
Pessler, Frank
TWINCORE; Zentrum für experimentelle und klinische Infectionsforsching GmbH, Feodor-Lynen Str. 17, 30625 Hannover, Germany.
We examined acceptability, preference and feasibility of collecting nasal and oropharyngeal swabs, followed by microbiome analysis, in a population-based study with 524 participants. Anterior nasal and oropharyngeal swabs were collected by certified personnel. In addition, participants self-collected nasal swabs at home four weeks later. Four swab types were compared regarding (1) participants' satisfaction and acceptance and (2) detection of microbial community structures based on deep sequencing of the 16 S rRNA gene V1-V2 variable regions. All swabbing methods were highly accepted. Microbial community structure analysis revealed 846 phylotypes, 46 of which were unique to oropharynx and 164 unique to nares. The calcium alginate tipped swab was found unsuitable for microbiome determinations. Among the remaining three swab types, there were no differences in oropharyngeal microbiomes detected and only marginal differences in nasal microbiomes. Microbial community structures did not differ between staff-collected and self-collected nasal swabs. These results suggest (1) that nasal and oropharyngeal swabbing are highly feasible methods for human population-based studies that include the characterization of microbial community structures in these important ecological niches, and (2) that self-collection of nasal swabs at home can be used to reduce cost and resources needed, particularly when serial measurements are to be taken.
2017-05-17T12:45:45Z
2017-05-17T12:45:45Z
2017-05-12
Article
Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study - findings from Pretest 1 of the German National Cohort. 2017, 7 (1):1855 Sci Rep
2045-2322
28500287
10.1038/s41598-017-01212-6
http://hdl.handle.net/10033/620922
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210132019-08-30T11:26:13Zcom_10033_211390com_10033_620601com_10033_620652col_10033_620666col_10033_211409col_10033_620603
2017-07-14T13:15:38Z
urn:hdl:10033/621013
Anti-nuclear autoantibodies in the general German population: prevalence and lack of association with selected cardiovascular and metabolic disorders-findings of a multicenter population-based study.
Akmatov, Manas K
Röber, Nadja
Ahrens, Wolfgang
Flesch-Janys, Dieter
Fricke, Julia
Greiser, Halina
Günther, Kathrin
Kaaks, Rudolf
Kemmling, Yvonne
Krone, Bastian
Linseisen, Jakob
Meisinger, Christa
Moebus, Susanne
Obi, Nadia
Guzman, Carlos A
Conrad, Karsten
Pessler, Frank
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
We determined the prevalence of anti-nuclear autoantibodies (ANAs) in the German adult population and examined the association between ANAs and cardiovascular and metabolic disorders.
2017-07-14T13:15:38Z
2017-07-14T13:15:38Z
2017-06-06
Article
Anti-nuclear autoantibodies in the general German population: prevalence and lack of association with selected cardiovascular and metabolic disorders-findings of a multicenter population-based study. 2017, 19 (1):127 Arthritis Res. Ther.
1478-6362
28587625
10.1186/s13075-017-1338-5
http://hdl.handle.net/10033/621013
Arthritis research & therapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210712019-08-30T11:27:16Zcom_10033_620626com_10033_620601col_10033_620627col_10033_620603
2017-08-22T14:00:30Z
urn:hdl:10033/621071
Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection.
Preusse, Matthias
Schughart, Klaus
Pessler, Frank
Expression of host microRNAs (miRNAs) changes markedly during influenza A virus (IAV) infection of natural and adaptive hosts, but their role in genetically determined host susceptibility to IAV infection has not been explored. We, therefore, compared pulmonary miRNA expression during IAV infection in two inbred mouse strains with differential susceptibility to IAV infection.
2017-08-22T14:00:30Z
2017-08-22T14:00:30Z
2017
Article
Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection. 2017, 8:246 Front Immunol
1664-3224
28377766
10.3389/fimmu.2017.00246
http://hdl.handle.net/10033/621071
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212132019-01-03T07:58:16Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
2017-12-20T14:12:08Z
urn:hdl:10033/621213
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori
Filomena, Angela
Pessler, Frank
Akmatov, Manas K
Krause, Gérard
Duffy, Darragh
Gärtner, Barbara
Gerhard, Markus
Albert, Matthew
Joos, Thomas
Schneiderhan-Marra, Nicole
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-12-20T14:12:08Z
2017-12-20T14:12:08Z
2017-10-30
Article
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori 2017, 6 (4):14 High-Throughput
2571-5135
29855458
10.3390/ht6040014
http://hdl.handle.net/10033/621213
High-Throughput
http://www.mdpi.com/2571-5135/6/4/14
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212202019-08-30T11:25:11Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
2018-01-03T08:52:06Z
urn:hdl:10033/621220
Hepatitis B vaccination timing: results from demographic health surveys in 47 countries.
Schweitzer, Aparna
Akmatov, Manas K
Krause, Gerard
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
To examine the impact of hepatitis B vaccination schedules and types of vaccines on hepatitis B vaccination timing.
2018-01-03T08:52:06Z
2018-01-03T08:52:06Z
2017-03-01
Article
Hepatitis B vaccination timing: results from demographic health surveys in 47 countries. 2017, 95 (3):199-209G Bull. World Health Organ.
1564-0604
28250533
10.2471/BLT.16.178822
http://hdl.handle.net/10033/621220
Bulletin of the World Health Organization
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212212019-08-30T11:35:13Zcom_10033_620601col_10033_620603
2018-01-03T09:14:00Z
urn:hdl:10033/621221
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus.
De Jaime-Soguero, Anchel
Aulicino, Francesco
Ertaylan, Gokhan
Griego, Anna
Cerrato, Aniello
Tallam, Aravind
Del Sol, Antonio
Cosma, Maria Pia
Lluis, Frederic
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Understanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naïve pluripotency by holding back differentiation. The canonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/β-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of β-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors.
2018-01-03T09:14:00Z
2018-01-03T09:14:00Z
2017-03
Article
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. 2017, 13 (3):e1006682 PLoS Genet.
1553-7404
28346462
10.1371/journal.pgen.1006682
http://hdl.handle.net/10033/621221
PLoS genetics
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213412019-08-30T11:34:22Zcom_10033_620659com_10033_620601col_10033_620661col_10033_620603
2018-04-10T08:09:30Z
urn:hdl:10033/621341
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck).
Samir, M
Hamed, M
Abdallah, F
Kinh Nguyen, V
Hernandez-Vargas, E A
Seehusen, F
Baumgärtner, W
Hussein, A
Ali, A A H
Pessler,, F
TWINCORE, Zentrum für experimentelle uns klinische Ifektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to cause major problems in poultry and can, although rarely, cause human infection. Being enzootic in domestic poultry, Egyptian isolates are continuously evolving, and novel clades vary in their pathogenicity in avian hosts. Considering the importance of domestic ducks as natural hosts of HPAI H5N1 viruses and their likelihood of physical contact with other avian hosts and humans, it is of utmost importance to characterize the pathogenicity of newly emerged HPAI strains in the domestic duck. The most recently identified Egyptian clade 2.2.1.2 HPAI H5N1 viruses have been isolated from naturally infected pigeons, turkeys and humans. However, essentially nothing is known about their pathogenicity in domestic ducks. We therefore characterized the pathogenicity of an Egyptian HPAI H5N1 isolate A/chicken/Faquos/amn12/2011 (clade 2.2.1.2) in Sudani duck, a domestic duck breed commonly reared in Egypt. While viral transcription (HA mRNA) was highest in lung, heart and kidney peaking between 40 and 48 hpi, lower levels were detected in brain. Weight loss of infected ducks started at 16 hpi and persisted until 120 hpi. The first severe clinical signs were noted by 32 hpi and peaked in severity at 72 and 96 hpi. Haematological analyses showed a decline in total leucocytes, granulocytes, platelets and granulocyte/lymphocyte ratio, but lymphocytosis. Upon necropsy, lesions were obvious in heart, liver, spleen and pancreas and consisted mainly of necrosis and petechial haemorrhage. Histologically, lungs were the most severely affected organs, whereas brain only showed mild neuronal degeneration and gliosis at 48 hpi despite obvious neurological clinical signs. Taken together, our results provide first evidence that this HPAI H5N1 isolate (clade 2.2.1.2) is highly pathogenic to Sudani ducks and highlight the importance of this breed as potential reservoir and disseminator of HPAI strains from this clade.
2018-04-10T08:09:30Z
2018-04-10T08:09:30Z
2018-01-24
Article
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck). 2018 Transbound Emerg Dis
1865-1682
29363279
10.1111/tbed.12816
http://hdl.handle.net/10033/621341
Transboundary and emerging diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213492019-08-30T11:25:11Zcom_10033_620601com_10033_311308col_10033_620721col_10033_620603
2018-04-12T13:50:11Z
urn:hdl:10033/621349
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation.
Kuhn, Maike
Sühs, Kurt-Wolfram
Akmatov, Manas K
Klawonn, Frank
Wang, Junxi
Skripuletz, Thomas
Kaever, Volkhard
Stangel, Martin
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Varicella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation.
2018-04-12T13:50:11Z
2018-04-12T13:50:11Z
2018-01-17
Article
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. 2018, 15 (1):20 J Neuroinflammation
1742-2094
29343258
10.1186/s12974-017-1041-0
http://hdl.handle.net/10033/621349
Journal of neuroinflammation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213732019-08-30T11:33:29Zcom_10033_620601col_10033_620603
2018-05-16T12:56:46Z
urn:hdl:10033/621373
Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture.
Olmer, Ruth
Engels, Lena
Usman, Abdulai
Menke, Sandra
Malik, Muhammad Nasir Hayat
Pessler, Frank
Göhring, Gudrun
Bornhorst, Dorothee
Bolten, Svenja
Abdelilah-Seyfried, Salim
Scheper, Thomas
Kempf, Henning
Zweigerdt, Robert
Martin, Ulrich
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Endothelial cells (ECs) are involved in a variety of cellular responses. As multifunctional components of vascular structures, endothelial (progenitor) cells have been utilized in cellular therapies and are required as an important cellular component of engineered tissue constructs and in vitro disease models. Although primary ECs from different sources are readily isolated and expanded, cell quantity and quality in terms of functionality and karyotype stability is limited. ECs derived from human induced pluripotent stem cells (hiPSCs) represent an alternative and potentially superior cell source, but traditional culture approaches and 2D differentiation protocols hardly allow for production of large cell numbers. Aiming at the production of ECs, we have developed a robust approach for efficient endothelial differentiation of hiPSCs in scalable suspension culture. The established protocol results in relevant numbers of ECs for regenerative approaches and industrial applications that show in vitro proliferation capacity and a high degree of chromosomal stability.
2018-05-16T12:56:46Z
2018-05-16T12:56:46Z
2018-05-08
Article
Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture. 2018, 10 (5):1657-1672 Stem Cell Reports
2213-6711
29681541
10.1016/j.stemcr.2018.03.017
http://hdl.handle.net/10033/621373
Stem cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213922019-08-30T11:26:37Zcom_10033_620626com_10033_620601col_10033_620629col_10033_620603
2018-06-05T12:52:50Z
urn:hdl:10033/621392
Early Lymphocyte Loss and Increased Granulocyte/Lymphocyte Ratio Predict Systemic Spread of in a Mouse Model of Acute Skin Infection.
Loof, Torsten G
Sohail, Aaqib
Bahgat, Mahmoud M
Tallam, Aravind
Arshad, Haroon
Akmatov, Manas K
Pils, Marina C
Heise, Ulrike
Beineke, Andreas
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Streptococcus pyogenes
biomarker
leukocytes
lymphopenia
sepsis
skin infection
Group A streptococci may induce lymphopenia, but the value of lymphocyte loss as early biomarkers for systemic spread and severe infection has not been examined systematically. We evaluated peripheral blood cell indices as biomarkers for severity and spread of infection in a mouse model of skin infection, using two isolates of greatly differing virulence. Internal organs were examined histologically. After subcutaneous inoculation, strain AP1 disseminated rapidly to peripheral blood and internal organs, causing frank sepsis. In contrast, seeding of internal organs by 5448 was mild, this strain could not be isolated from blood, and infection remained mostly localized to skin. Histopathologic examination of liver revealed microvesicular fatty change (steatosis) in AP1 infection, and examination of spleen showed elevated apoptosis and blurring of the white pulp/red pulp border late (40 h post infection) in AP1 infection. Both strains caused profound lymphopenia, but lymphocyte loss was more rapid early in AP1 infection, and lymphocyte count at 6 h post infection was the most accurate early marker for AP1 infection (area under the receiver operator curve [AUC] = 0.93), followed by the granulocyte/lymphocyte ratio (AUC = 0.89). The results suggest that virulence of correlates with the degree of early lymphopenia and underscore the value of peripheral blood indices to predict severity of bacterial infections in mice. Early lymphopenia and elevated granulocyte/lymphocyte ratio merit further investigation as biomarkers for systemic spread of skin infections in humans and, possibly, related pyogenic streptococci in humans and animals.
2018-06-05T12:52:50Z
2018-06-05T12:52:50Z
Article
29707522
http://hdl.handle.net/10033/621392
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
oai:repository.helmholtz-hzi.de:10033/6214532019-08-30T11:29:14Zcom_10033_620601col_10033_620603
2018-08-27T08:47:40Z
urn:hdl:10033/621453
NS Segment of a 1918 Influenza A Virus-Descendent Enhances Replication of H1N1pdm09 and Virus-Induced Cellular Immune Response in Mammalian and Avian Systems.
Petersen, Henning
Mostafa, Ahmed
Tantawy, Mohamed A
Iqbal, Azeem A
Hoffmann, Donata
Tallam, Aravind
Selvakumar, Balachandar
Pessler, Frank
Beer, Martin
Rautenschlein, Silke
Pleschka, Stephan
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
H1N1pdm09
NS segment
influenza virus
innate immunity
reassortment
The 2009 pandemic influenza A virus (IAV) H1N1 strain (H1N1pdm09) has widely spread and is circulating in humans and swine together with other human and avian IAVs. This fact raises the concern that reassortment between H1N1pdm09 and co-circulating viruses might lead to an increase of H1N1pdm09 pathogenicity in different susceptible host species. Herein, we explored the potential of different NS segments to enhance the replication dynamics, pathogenicity and host range of H1N1pdm09 strain A/Giessen/06/09 (Gi-wt). The NS segments were derived from (i) human H1N1- and H3N2 IAVs, (ii) highly pathogenic- (H5- or H7-subtypes) or (iii) low pathogenic avian influenza viruses (H7- or H9-subtypes). A significant increase of growth kinetics in A549 (human lung epithelia) and NPTr (porcine tracheal epithelia) cells was only noticed
2018-08-27T08:47:40Z
2018-08-27T08:47:40Z
2018-01-01
Article
1664-302X
29623073
10.3389/fmicb.2018.00526
http://hdl.handle.net/10033/621453
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers in microbiology
oai:repository.helmholtz-hzi.de:10033/6214672019-08-30T11:30:30Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
2018-09-04T12:07:08Z
urn:hdl:10033/621467
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori.
Filomena, Angela
Pessler, Frank
Akmatov, Manas K
Krause, Gérard
Duffy, Darragh
Gärtner, Barbara
Gerhard, Markus
Albert, Matthew L
Joos, Thomas O
Schneiderhan-Marra, Nicole
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Helicobacter pylori
Toxoplasma gondii
cytomegalovirus (CMV)
hepatitis
multi-pathogen assay
multiplex
seroprevalence
serotest
The spread of infectious diseases and vaccination history are common subjects of epidemiological and immunological research studies. Multiplexed serological assays are useful tools for assessing both current and previous infections as well as vaccination efficacy. We developed a serological multi-pathogen assay for hepatitis A, B and C virus, cytomegalovirus (CMV),
2018-09-04T12:07:08Z
2018-09-04T12:07:08Z
2017-10-30
Article
2571-5135
29855458
10.3390/ht6040014
http://hdl.handle.net/10033/621467
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
High-throughput
oai:repository.helmholtz-hzi.de:10033/6215902019-08-30T11:29:44Zcom_10033_620626com_10033_620601com_10033_620618col_10033_620629col_10033_620603col_10033_620621
2018-11-28T10:27:41Z
urn:hdl:10033/621590
An Interferon Signature Discriminates Pneumococcal From Staphylococcal Pneumonia.
Strehlitz, Anja
Goldmann, Oliver
Pils, Marina C
Pessler, Frank
Medina, Eva
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Staphylococcus aureus
Streptococcus pneumoniae
biomarkers
interferon
pneumonia
transcriptome
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). Despite the low prevalence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA), CAP patients often receive empirical antibiotic therapy providing coverage for MRSA such as vancomycin or linezolid. An early differentiation between S. pneumoniae and S. aureus pneumonia can help to reduce the use of unnecessary antibiotics. The objective of this study was to identify candidate biomarkers that can discriminate pneumococcal from staphylococcal pneumonia. A genome-wide transcriptional analysis of lung and peripheral blood performed in murine models of S. pneumoniae and S. aureus lung infection identified an interferon signature specifically associated with S. pneumoniae infection. Prediction models built using a support vector machine and Monte Carlo cross-validation, identified the combination of the interferon-induced chemokines CXCL9 and CXCL10 serum concentrations as the set of biomarkers with best sensitivity, specificity, and predictive power that enabled an accurate discrimination between S. pneumoniae and S. aureus pneumonia. The predictive performance of these biomarkers was further validated in an independent cohort of mice. This study highlights the potential of serum CXCL9 and CXCL10 biomarkers as an adjunctive diagnostic tool that could facilitate prompt and correct pathogen-targeted therapy in CAP patients.
2018-11-28T10:27:41Z
2018-11-28T10:27:41Z
2018-01-01
Article
1664-3224
29988532
10.3389/fimmu.2018.01424
http://hdl.handle.net/10033/621590
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6216912019-11-21T12:02:26Zcom_10033_620601col_10033_620603
2019-02-15T13:11:44Z
urn:hdl:10033/621691
Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis.
Ratuszny, Dominica
Sühs, Kurt-Wolfram
Novoselova, Natalia
Kuhn, Maike
Kaever, Volkhard
Skripuletz, Thomas
Pessler, Frank
Stangel, Martin
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CNS infection
biomarker
cerebrospinal fluid
enterovirus
meningitis
metabolomics
phosphatidylcholines
Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10), and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell’s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine PC.ae.C36.3, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, PC.ae.C36.3 alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising PC.ae.C36.3, PC.ae.C36.5, and PC.ae.C38.5 achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.
2019-02-15T13:11:44Z
2019-02-15T13:11:44Z
2019-01-15
Article
1422-0067
30650575
10.3390/ijms20020337
http://hdl.handle.net/10033/621691
International journal of molecular sciences
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MPDI
International journal of molecular sciences
oai:repository.helmholtz-hzi.de:10033/6216932019-02-16T01:23:08Zcom_10033_620601col_10033_620603
2019-02-15T13:56:34Z
urn:hdl:10033/621693
Discovery of Leptospira spp. seroreactive peptides using ORFeome phage display.
Ramli, Siti Roszilawati
Moreira, Gustavo M S G
Zantow, Jonas
Goris, Marga G A
Nguyen, Van Kinh
Novoselova, Natalia
Pessler, Frank
Hust, Michael
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Leptospirosis is the most common zoonotic disease worldwide. The diagnostic performance of a serological test for human leptospirosis is mainly influenced by the antigen used in the test assay. An ideal serological test should cover all serovars of pathogenic leptospires with high sensitivity and specificity and use reagents that are relatively inexpensive to produce and can be used in tropical climates. Peptide-based tests fulfil at least the latter two requirements, and ORFeome phage display has been successfully used to identify immunogenic peptides from other pathogens. Two ORFeome phage display libraries of the entire Leptospira spp. genomes from five local strains isolated in Malaysia and seven WHO reference strains were constructed. Subsequently, 18 unique Leptospira peptides were identified in a screen using a pool of sera from patients with acute leptospirosis. Five of these were validated by titration ELISA using different pools of patient or control sera. The diagnostic performance of these five peptides was then assessed against 16 individual sera from patients with acute leptospirosis and 16 healthy donors and was compared to that of two recombinant reference proteins from L. interrogans. This analysis revealed two peptides (SIR16-D1 and SIR16-H1) from the local isolates with good accuracy for the detection of acute leptospirosis (area under the ROC curve: 0.86 and 0.78, respectively; sensitivity: 0.88 and 0.94; specificity: 0.81 and 0.69), which was close to that of the reference proteins LipL32 and Loa22 (area under the ROC curve: 0.91 and 0.80; sensitivity: 0.94 and 0.81; specificity: 0.75 and 0.75). This analysis lends further support for using ORFeome phage display to identify pathogen-associated immunogenic peptides, and it suggests that this technique holds promise for the development of peptide-based diagnostics for leptospirosis and, possibly, of vaccines against this pathogen.
2019-02-15T13:56:34Z
2019-02-15T13:56:34Z
2019-01-01
Article
PLoS Negl Trop Dis. 2019 Jan 24;13(1):e0007131. doi:10.1371/journal.pntd.0007131
1935-2735
30677033
10.1371/journal.pntd.0007131
http://hdl.handle.net/10033/621693
Plos neglected tropical diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
PLOS
PLoS neglected tropical diseases
oai:repository.helmholtz-hzi.de:10033/6217012019-08-30T11:32:40Zcom_10033_620601col_10033_620603
2019-02-20T10:50:29Z
urn:hdl:10033/621701
Discovery of Leptospira spp. seroreactive peptides using ORFeome phage display.
Ramli, Siti Roszilawati
Moreira, Gustavo M S G
Zantow, Jonas
Goris, Marga G A
Nguyen, Van Kinh
Novoselova, Natalia
Pessler, Frank
Hust, Michael
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Leptospirosis is the most common zoonotic disease worldwide. The diagnostic performance of a serological test for human leptospirosis is mainly influenced by the antigen used in the test assay. An ideal serological test should cover all serovars of pathogenic leptospires with high sensitivity and specificity and use reagents that are relatively inexpensive to produce and can be used in tropical climates. Peptide-based tests fulfil at least the latter two requirements, and ORFeome phage display has been successfully used to identify immunogenic peptides from other pathogens. Two ORFeome phage display libraries of the entire Leptospira spp. genomes from five local strains isolated in Malaysia and seven WHO reference strains were constructed. Subsequently, 18 unique Leptospira peptides were identified in a screen using a pool of sera from patients with acute leptospirosis. Five of these were validated by titration ELISA using different pools of patient or control sera. The diagnostic performance of these five peptides was then assessed against 16 individual sera from patients with acute leptospirosis and 16 healthy donors and was compared to that of two recombinant reference proteins from L. interrogans. This analysis revealed two peptides (SIR16-D1 and SIR16-H1) from the local isolates with good accuracy for the detection of acute leptospirosis (area under the ROC curve: 0.86 and 0.78, respectively; sensitivity: 0.88 and 0.94; specificity: 0.81 and 0.69), which was close to that of the reference proteins LipL32 and Loa22 (area under the ROC curve: 0.91 and 0.80; sensitivity: 0.94 and 0.81; specificity: 0.75 and 0.75). This analysis lends further support for using ORFeome phage display to identify pathogen-associated immunogenic peptides, and it suggests that this technique holds promise for the development of peptide-based diagnostics for leptospirosis and, possibly, of vaccines against this pathogen.
2019-02-20T10:50:29Z
2019-02-20T10:50:29Z
2019-01-01
Article
1935-2735
30677033
10.1371/journal.pntd.0007131
http://hdl.handle.net/10033/621701
Plos neglected tropical diseases
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
PLOS
PLoS neglected tropical diseases
oai:repository.helmholtz-hzi.de:10033/6217252019-08-30T11:35:13Zcom_10033_620601col_10033_620603
2019-03-18T15:08:45Z
urn:hdl:10033/621725
Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral CNS infections.
Sühs, Kurt-Wolfram
Novoselova, Natalia
Kuhn, Maike
Seegers, Lena
Kaever, Volkhard
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Stangel, Martin
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
The tryptophan-kynurenine-NAD+ pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in CNS infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers. We measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 220 cerebrospinal fluid samples from patients with bacterial and viral (herpes simplex, varicella zoster, enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (anti-NMDA-R encephalitis, multiple sclerosis), and noninflamed controls (Bell's palsy, normal pressure hydrocephalus, Tourette syndrome). Kyn concentrations correlated strongly with CSF markers of neuroinflammation (leukocyte count, lactate, and blood-CSF-barrier dysfunction) and were highly increased in bacterial and viral CNS infections, but were low or undetectable in anti-NMDA-R encephalitis, multiple sclerosis, and controls. Trp was decreased mostly in viral CNS infections and neuroborreliosis. Multiple logistic regression analysis revealed combinations of Kyn, Trp and Kyn/Trp ratio with leukocyte count or lactate as accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation. The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation.
2019-03-18T15:08:45Z
2019-03-18T15:08:45Z
2019-02-05
Article
J Infect Dis. 2019 Feb 5. pii: 5307059. doi: 10.1093/infdis/jiz048.
1537-6613
30721966
10.1093/infdis/jiz048
http://hdl.handle.net/10033/621725
Journal of infectious diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Oxford University Press
The Journal of infectious diseases
oai:repository.helmholtz-hzi.de:10033/6217842019-08-30T11:33:26Zcom_10033_620601col_10033_620603
2019-05-20T11:36:36Z
urn:hdl:10033/621784
Helicobacter pylori seropositivity: Prevalence, Associations, and the Impact on Incident Metabolic Diseases/Risk Factors in the Population-Based KORA Study.
Wawro, Nina
Amann, Ute
Butt, Julia
Meisinger, Christa
Akmatov, Manas K
Pessler, Frank
Peters, Annette
Rathmann, Wolfgang
Kääb, Stefan
Waterboer, Tim
Linseisen, Jakob
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Helicobacter pylori
infection
metabolic diseases
multiplex serology
prevalence
Introduction:Helicobacter pylori (H. pylori) is a common infection and known risk factor for gastric cancer. We assessed cross-sectional and longitudinal associations to study the impact of H. pylori seropositivity on metabolic diseases. Methods:Helicobacter pylori seropositivity in serum samples of the KORA study was analyzed by multiplex serology. We calculated sex-specific prevalence of H. pylori seropositivity for the year 2007 based on the first follow-up survey (termed F4) of the KORA study S4. We identified factors associated with H. pylori seropositivity in the F4 survey. Further, we assessed relative risks of incident metabolic diseases/risk factors at the time of the second follow-up survey of S4 (termed FF4) and H. pylori seropositivity at the F4 survey as a determinant. Models were adjusted for age, sex, overweight status, physical activity, smoking status, education level, alcohol intake, and other metabolic diseases. Results: Based on 3,037 persons aged 32 to 82 years, the H. pylori prevalence for 2007 was 30.2% in men (n = 1,465) and 28.1% in women (n = 1,572). Increasing age, current smoking, low education and no alcohol intake were significantly associated with H. pylori seropositivity in the F4 survey. However, no association between H. pylori seropositivity and BMI, metabolic diseases (type 2 diabetes, hypertension and dyslipidemia, gout or increased uric acid) and gastrointestinal diseases (gastritis, inflammatory bowel disease, and gastric or duodenal ulcer) was observed. No significant associations between H. pylori seropositivity and one of the five investigated incident metabolic diseases/risk factors were detected in the longitudinal analysis. Conclusion: We identified associations between age, smoking, education and alcohol intake and H. pylori seropositivity but no impact of H. pylori seropositivity on incident metabolic diseases/risk factors.
2019-05-20T11:36:36Z
2019-05-20T11:36:36Z
2019-01-01
Article
Front Public Health. 2019 Apr 24;7:96. doi: 10.3389/fpubh.2019.00096. eCollection 2019.
2296-2565
31069210
10.3389/fpubh.2019.00096
http://hdl.handle.net/10033/621784
Frontiers in Public Health
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Frontiers
Frontiers in public health
oai:repository.helmholtz-hzi.de:10033/6219142019-08-30T11:27:14Zcom_10033_620601col_10033_620603
2019-08-21T10:41:11Z
urn:hdl:10033/621914
Self-reported diabetes and herpes zoster are associated with a weak humoral response to the seasonal influenza A H1N1 vaccine antigen among the elderly.
Akmatov, Manas K
Riese, Peggy
Trittel, Stephanie
May, Marcus
Prokein, Jana
Illig, Thomas
Schindler, Christoph
Guzmán, Carlos A
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Diabetes
Elderly
Fluad®
Herpes zoster
Influenza vaccination
BACKGROUND:
The immune response to seasonal influenza vaccines decreases with advancing age. Therefore, an adjuvanted inactivated trivalent influenza vaccine (Fluad®) exists for elderly individuals. Fluad® is more immunogenic and efficacious than conventional influenza vaccines. However, the immune response varies and may still result in high frequencies of poor responders. Therefore, we aimed to a) examine the prevalence of a weak response to Fluad® and b) identify potential risk factors.
METHODS:
A prospective population-based study among individuals 65-80 years old was conducted in 2015/2016 in Hannover, Germany (n = 200). Hemagglutination-inhibition titers 21 days after vaccination with Fluad® served as indicator of vaccine responsiveness.
RESULTS:
The percentage of vaccinees with an inadequate vaccine response varied depending on the influenza strain: it was lowest for H3N2 (13.5%; 95% CI, 9.4-18.9%), intermediate for B strain (37.0%; 30.6-43.9%), and highest for H1N1 (49.0%; 42.2-55.9%). The risk of a weak response to the influenza A H1N1 strain was independently associated with self-reported diabetes (AOR, 4.64; 95% CI, 1.16-18.54), a history of herpes zoster (2.27; 1.01-5.10) and, to a much lesser extent, increasing age (change per year, 1.08; 0.99-1.16). In addition, herpes zoster was the only risk factor for a weak response to the H3N2 antigen (AOR, 3.12; 1.18-8.23). We found no significant association between sex, Body Mass Index, cancer, hypertension, heart attack and CMV seropositivity and a weak response to these two influenza A antigens. Despite its occurence in over one third of vaccinees, none of the variables examined proved to be risk factors for a weak response to the B antigen.
CONCLUSIONS:
A considerable proportion of elderly individuals displayed a weak vaccine response to this adjuvanted seasonal influenza vaccine and further efforts are thus needed to improve immune responses to influenza vaccination among the elderly. Diabetes and herpes zoster were identified as potentially modifiable risk factors for a poor vaccine response against influenza A antigens, but the results also reveal the need for broader investigations to identify risk factors for inadequate responses to influenza B antigens.
2019-08-21T10:41:11Z
2019-08-21T10:41:11Z
2019-07-23
Article
BMC Infect Dis. 2019 Jul 23;19(1):656. doi: 10.1186/s12879-019-4214-x.
1471-2334
31337344
10.1186/s12879-019-4214-x
http://hdl.handle.net/10033/621914
BMC Infectious Diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BioMedCentral
BMC infectious diseases
oai:repository.helmholtz-hzi.de:10033/6219642019-10-05T11:57:51Zcom_10033_620601col_10033_620603
2019-10-04T13:45:05Z
urn:hdl:10033/621964
Crystal structure of -aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.
Chen, Fangfang
Lukat, Peer
Iqbal, Azeem Ahmed
Saile, Kyrill
Kaever, Volkhard
van den Heuvel, Joop
Blankenfeldt, Wulf
Büssow, Konrad
Pessler, Frank
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
cis-aconitate
decarboxylase
enzymology
itaconic acid
macrophage
cis-Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis-aconitate to itaconate and plays central roles in linking innate immunity with metabolism and in the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated the crystal structures of human and murine CADs and compared their enzymological properties to CAD from A. terreus Recombinant CAD is fully active in vitro without a cofactor. Murine CAD has the highest catalytic activity, whereas Aspergillus CAD is best adapted to a more acidic pH. CAD is not homologous to any known decarboxylase and appears to have evolved from prokaryotic enzymes that bind negatively charged substrates. CADs are homodimers, the active center is located in the interface between 2 distinct subdomains, and structural modeling revealed conservation in zebrafish and Aspergillus We identified 8 active-site residues critical for CAD function and rare naturally occurring human mutations in the active site that abolished CAD activity, as well as a variant (Asn152Ser) that increased CAD activity and is common (allele frequency 20%) in African ethnicity. These results open the way for 1) assessing the potential impact of human CAD variants on disease risk at the population level, 2) developing therapeutic interventions to modify CAD activity, and 3) improving CAD efficiency for biotechnological production of itaconic acid.
2019-10-04T13:45:05Z
2019-10-04T13:45:05Z
2019-09-23
Article
Proc Natl Acad Sci U S A. 2019 Sep 23. pii: 1908770116. doi:10.1073/pnas.1908770116.
1091-6490
31548418
10.1073/pnas.1908770116
http://hdl.handle.net/10033/621964
Proceedings of the National Academy of sciences
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
National Academy of Sciences
Proceedings of the National Academy of Sciences of the United States of America
oai:repository.helmholtz-hzi.de:10033/6219842019-10-19T01:32:04Zcom_10033_620601col_10033_620603
2019-10-18T13:14:10Z
urn:hdl:10033/621984
Electro-Microbiology as a Promising Approach Towards Renewable Energy and Environmental Sustainability
Ali, Jafar
Sohail, Aaqib
Wang, Lei
Rizwan Haider, Muhammad
Mulk, Shahi
Pan, Gang
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Microbial electrochemical technologies provide sustainable wastewater treatment and energy production. Despite significant improvements in the power output of microbial fuel cells (MFCs), this technology is still far from practical applications. Extracting electrical energy and harvesting valuable products by electroactive bacteria (EAB) in bioelectrochemical systems (BESs) has emerged as an innovative approach to address energy and environmental challenges. Thus, maximizing power output and resource recovery is highly desirable for sustainable systems. Insights into the electrode-microbe interactions may help to optimize the performance of BESs for envisioned applications, and further validation by bioelectrochemical techniques is a prerequisite to completely understand the electro-microbiology. This review summarizes various extracellular electron transfer mechanisms involved in BESs. The significant role of characterization techniques in the advancement of the electro-microbiology field is discussed. Finally, diverse applications of BESs, such as resource recovery, and contributions to the pursuit of a more sustainable society are also highlighted.
2019-10-18T13:14:10Z
2019-10-18T13:14:10Z
2018-07-12
Article
1996-1073
10.3390/en11071822
http://hdl.handle.net/10033/621984
Energies
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MDPI AG
11
7
1822
oai:repository.helmholtz-hzi.de:10033/6220332019-11-28T01:59:48Zcom_10033_620601col_10033_620603
2019-11-27T09:16:59Z
urn:hdl:10033/622033
Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia.
Arshad, Haroon
Alfonso, Juan Carlos López
Franke, Raimo
Michaelis, Katina
Araujo, Leonardo
Habib, Aamna
Zboromyrska, Yuliya
Lücke, Eva
Strungaru, Emilia
Akmatov, Manas K
Hatzikirou, Haralampos
Meyer-Hermann, Michael
Petersmann, Astrid
Nauck, Matthias
Brönstrup, Mark
Bilitewski, Ursula
Abel, Laurent
Sievers, Jorg
Vila, Jordi
Illig, Thomas
Schreiber, Jens
Pessler, Frank
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Biomarkers
Chronic obstructive pulmonary disease
Community-acquired pneumonia
Glycerophospholipids
Infection
Lipidomics
Lung disease
Mass spectrometry
Metabolism
Metabolomics
Sphingomyelinase
BACKGROUND:
There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage.
METHODS:
We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls.
RESULTS:
Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution.
CONCLUSIONS:
The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP
2019-11-27T09:16:59Z
2019-11-27T09:16:59Z
2019-11-11
Article
J Transl Med. 2019 Nov 11;17(1):365. doi: 10.1186/s12967-019-2112-z.
1479-5876
31711507
10.1186/s12967-019-2112-z
http://hdl.handle.net/10033/622033
Journal of translational medicine
en
info:eu-repo/grantAgreement/EC/FP7/115523
http://creativecommons.org/licenses/by-nc-sa/4.0/
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
Wiley
Journal of translational medicine
oai:repository.helmholtz-hzi.de:10033/6220522019-12-20T01:59:12Zcom_10033_620601com_10033_620636col_10033_620603col_10033_620638
2019-12-19T14:28:25Z
urn:hdl:10033/622052
Reprogramming of Small Noncoding RNA Populations in Peripheral Blood Reveals Host Biomarkers for Latent and Active Mycobacterium tuberculosis Infection.
de Araujo, Leonardo Silva
Ribeiro-Alves, Marcelo
Leal-Calvo, Thyago
Leung, Janaína
Durán, Verónica
Samir, Mohamed
Talbot, Steven
Tallam, Aravind
Mello, Fernanda Carvalho de Queiroz
Geffers, Robert
Saad, Maria Helena Féres
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
RNA
biomarkers
biosignature
incipient tuberculosis
miRNA
piRNA
snRNA
sncRNA
snoRNA
subclinical tuberculosis
transcriptome
tuberculosis
In tuberculosis (TB), as in other infectious diseases, studies of small noncoding RNAs (sncRNA) in peripheral blood have focused on microRNAs (miRNAs) but have neglected the other major sncRNA classes in spite of their potential functions in host gene regulation. Using RNA sequencing of whole blood, we have therefore determined expression of miRNA, PIWI-interacting RNA (piRNA), small nucleolar RNA (snoRNA), and small nuclear RNA (snRNA) in patients with TB (n = 8), latent TB infection (LTBI; n = 21), and treated LTBI (LTBItt; n = 6) and in uninfected exposed controls (ExC; n = 14). As expected, sncRNA reprogramming was greater in TB than in LTBI, with the greatest changes seen in miRNA populations. However, substantial dynamics were also evident in piRNA and snoRNA populations. One miRNA and 2 piRNAs were identified as moderately accurate (area under the curve [AUC] = 0.70 to 0.74) biomarkers for LTBI, as were 1 miRNA, 1 piRNA, and 2 snoRNAs (AUC = 0.79 to 0.91) for accomplished LTBI treatment. Logistic regression identified the combination of 4 sncRNA (let-7a-5p, miR-589-5p, miR-196b-5p, and SNORD104) as a highly sensitive (100%) classifier to discriminate TB from all non-TB groups. Notably, it reclassified 8 presumed LTBI cases as TB cases, 5 of which turned out to have features of Mycobacterium tuberculosis infection on chest radiographs. SNORD104 expression decreased during M. tuberculosis infection of primary human peripheral blood mononuclear cells (PBMC) and M2-like (P = 0.03) but not M1-like (P = 0.31) macrophages, suggesting that its downregulation in peripheral blood in TB is biologically relevant. Taken together, the results demonstrate that snoRNA and piRNA should be considered in addition to miRNA as biomarkers and pathogenesis factors in the various stages of TB.IMPORTANCE Tuberculosis is the infectious disease with the worldwide largest disease burden and there remains a great need for better diagnostic biomarkers to detect latent and active M. tuberculosis infection. RNA molecules hold great promise in this regard, as their levels of expression may differ considerably between infected and uninfected subjects. We have measured expression changes in the four major classes of small noncoding RNAs in blood samples from patients with different stages of TB infection. We found that, in addition to miRNAs (which are known to be highly regulated in blood cells from TB patients), expression of piRNA and snoRNA is greatly altered in both latent and active TB, yielding promising biomarkers. Even though the functions of many sncRNA other than miRNA are still poorly understood, our results strongly suggest that at least piRNA and snoRNA populations may represent hitherto underappreciated players in the different stages of TB infection.
2019-12-19T14:28:25Z
2019-12-19T14:28:25Z
2019-12-03
Article
MBio. 2019 Dec 3;10(6). pii: mBio.01037-19. doi: 10.1128/mBio.01037-19.
2150-7511
31796535
10.1128/mBio.01037-19
http://hdl.handle.net/10033/622052
mBIO
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
America Society of Microbiology (ASM)
mBio
oai:repository.helmholtz-hzi.de:10033/6220912020-01-18T02:09:10Zcom_10033_620601col_10033_620603
2020-01-17T13:46:03Z
urn:hdl:10033/622091
Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis.
de Araujo, Leonardo Silva
Pessler, Kevin
Sühs, Kurt-Wolfram
Novoselova, Natalia
Klawonn, Frank
Kuhn, Maike
Kaever, Volkhard
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Stangel, Martin
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Biomarker
Brain
Diagnosis
Encephalitis
Infection
Lecithin
Lipidomics
Lipids
Meningitis
Metabolomics
BACKGROUND: The timely diagnosis of bacterial meningitis is of utmost importance due to the need to institute antibiotic treatment as early as possible. Moreover, the differentiation from other causes of meningitis/encephalitis is critical because of differences in management such as the need for antiviral or immunosuppressive treatments. Considering our previously reported association between free membrane phospholipids in cerebrospinal fluid (CSF) and CNS involvement in neuroinfections we evaluated phosphatidylcholine PC ae C44:6, an integral constituent of cell membranes, as diagnostic biomarker for bacterial meningitis.
METHODS: We used tandem mass spectrometry to measure concentrations of PC ae C44:6 in cell-free CSF samples (n = 221) from patients with acute bacterial meningitis, neuroborreliosis, viral meningitis/encephalitis (herpes simplex virus, varicella zoster virus, enteroviruses), autoimmune neuroinflammation (anti-NMDA-receptor autoimmune encephalitis, multiple sclerosis), facial nerve and segmental herpes zoster (shingles), and noninflammatory CNS disorders (Bell's palsy, Tourette syndrome, normal pressure hydrocephalus).
RESULTS: PC ae C44:6 concentrations were significantly higher in bacterial meningitis than in all other diagnostic groups, and were higher in patients with a classic bacterial meningitis pathogen (e.g. Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus) than in those with less virulent or opportunistic pathogens as causative agents (P = 0.026). PC ae C44:6 concentrations were only moderately associated with CSF cell count (Spearman's ρ = 0.45; P = 0.009), indicating that they do not merely reflect neuroinflammation. In receiver operating characteristic curve analysis, PC ae C44:6 equaled CSF cell count in the ability to distinguish bacterial meningitis from viral meningitis/encephalitis and autoimmune CNS disorders (AUC 0.93 both), but had higher sensitivity (91% vs. 41%) and negative predictive value (98% vs. 89%). A diagnostic algorithm comprising cell count, lactate and PC ae C44:6 had a sensitivity of 97% (specificity 87%) and negative predictive value of 99% (positive predictive value 61%) and correctly diagnosed three of four bacterial meningitis samples that were misclassified by cell count and lactate due to low values not suggestive of bacterial meningitis.
CONCLUSIONS: Increased CSF PC ae C44:6 concentrations in bacterial meningitis likely reflect ongoing CNS cell membrane stress or damage and have potential as additional, sensitive biomarker to diagnose bacterial meningitis in patients with less pronounced neuroinflammation.
2020-01-17T13:46:03Z
2020-01-17T13:46:03Z
2020-01-07
Article
J Transl Med. 2020 Jan 7;18(1):9. doi: 10.1186/s12967-019-02179-w.
1479-5876
31910875
10.1186/s12967-019-02179-w
http://hdl.handle.net/10033/622091
l: Journal of Translational Medicine
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BioMed Central (BMC)
Journal of translational medicine
oai:repository.helmholtz-hzi.de:10033/6222032020-03-14T02:00:44Zcom_10033_620601col_10033_620603
2020-03-13T09:15:40Z
urn:hdl:10033/622203
Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo.
Reinke, Sören
Linge, Mary
Diebner, Hans H
Luksch, Hella
Glage, Silke
Gocht, Anne
Robertson, Avril A B
Cooper, Matthew A
Hofmann, Sigrun R
Naumann, Ronald
Sarov, Mihail
Behrendt, Rayk
Roers, Axel
Pessler, Frank
Roesler, Joachim
Rösen-Wolff, Angela
Winkler, Stefan
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
NF-κB
Rip2
TNF-α
caspase-1
enzymatic activity
non-canonical caspase-1 signaling
Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1β and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1β production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1β processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1-/- mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo.
2020-03-13T09:15:40Z
2020-03-13T09:15:40Z
Article
Cell Rep. 2020 Feb 25;30(8):2501-2511.e5. doi: 10.1016/j.celrep.2020.01.090.
32101731
10.1016/j.celrep.2020.01.090
http://hdl.handle.net/10033/622203
2211-1247
Cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier/ Cell Press
30
8
2501
2511.e5
Cell reports
United States
oai:repository.helmholtz-hzi.de:10033/6222552020-05-12T02:36:12Zcom_10033_620601col_10033_620603
2020-05-11T14:53:34Z
urn:hdl:10033/622255
Presence of hepatitis B virus in synovium and its clinical significance in rheumatoid arthritis.
Chen, Yu-Lan
Jing, Jun
Mo, Ying-Qian
Ma, Jian-Da
Yang, Li-Juan
Chen, Le-Feng
Zhang, Xiang
Yan, Tao
Zheng, Dong-Hui
Pessler, Frank
Dai, Lie
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Hepatitis B virus
Radiographic progression
Rheumatoid arthritis
Synovial biopsy
Synovium
BACKGROUND:
Previous studies have revealed that hepatitis B virus (HBV) infection may be related to rheumatoid arthritis (RA), but there are no studies on the presence of HBV antigens or nucleic acid in synovium from patients with RA with HBV infection. In the present study, we investigated the presence of HBV in the synovium and its clinical significance in RA.
METHODS:
Fifty-seven consecutive patients with active RA (Disease Activity Score 28-joint assessment based on C-reactive protein ≥ 2.6) and available synovial tissue who had completed 1 year of follow-up were recruited from a prospective cohort. The patients were divided into chronic HBV infection (CHB, n = 11) and non-CHB groups according to baseline HBV infection status. Clinical data were collected at baseline and at 1-, 3-, 6-, and 12-month follow-up. Radiographic changes of hand/wrist at baseline and month 12 were assessed with the Sharp/van der Heijde-modified Sharp score (mTSS). HBV in synovium was determined by immunohistochemical staining for hepatitis B virus surface antigen and hepatitis B virus core antigen (HBcAg) and by nested PCR for the HBV S gene.
RESULTS:
HBcAg was found in the synovium of patients with RA with CHB (7 of 11, 64%), which was confirmed by PCR for the HBV S gene. Compared with the non-CHB group, more CD68-positive macrophages, CD20-positive B cells, and CD15-positive neutrophils infiltrated the synovium in the CHB group (all p < 0.05). There were smaller improvements from baseline in most disease activity indicators mainly at month 12, and a significantly higher percentage of CHB patients experienced 1-year radiographic progression (ΔmTSS ≥ 0.5 unit/yr, 64% vs. 26%, p = 0.024). Multivariate logistic regression analysis showed that CHB status (OR 14.230, 95% CI 2.213-95.388; p = 0.006) and the density of synovial CD68-positive macrophages (OR 1.002, 95% CI 1.001-1.003; p = 0.003) were independently associated with 1-year radiographic progression.
CONCLUSIONS:
The presence of HBV in RA synovium may be involved in the pathogenesis of local lesions and exacerbate disease progression in RA.
2020-05-11T14:53:34Z
2020-05-11T14:53:34Z
2018-06-19
Article
Other
Arthritis Res Ther. 2018 Jun 19;20(1):130. doi: 10.1186/s13075-018-1623-y.
29921328
10.1186/s13075-018-1623-y
http://hdl.handle.net/10033/622255
1478-6362
Arthritis research & therapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BMC
20
1
130
Arthritis research & therapy
England
oai:repository.helmholtz-hzi.de:10033/6222542020-05-12T02:36:04Zcom_10033_620601col_10033_620603
2020-05-11T14:46:10Z
urn:hdl:10033/622254
Presence of hepatitis B virus in synovium and its clinical significance in rheumatoid arthritis.
Chen, Yu-Lan
Jing, Jun
Mo, Ying-Qian
Ma, Jian-Da
Yang, Li-Juan
Chen, Le-Feng
Zhang, Xiang
Yan, Tao
Zheng, Dong-Hui
Pessler, Frank
Dai, Lie
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Hepatitis B virus
Radiographic progression
Rheumatoid arthritis
Synovial biopsy
Synovium
Previous studies have revealed that hepatitis B virus (HBV) infection may be related to rheumatoid arthritis (RA), but there are no studies on the presence of HBV antigens or nucleic acid in synovium from patients with RA with HBV infection. In the present study, we investigated the presence of HBV in the synovium and its clinical significance in RA.
METHODS: Fifty-seven consecutive patients with active RA (Disease Activity Score 28-joint assessment based on C-reactive protein ≥ 2.6) and available synovial tissue who had completed 1 year of follow-up were recruited from a prospective cohort. The patients were divided into chronic HBV infection (CHB, n = 11) and non-CHB groups according to baseline HBV infection status. Clinical data were collected at baseline and at 1-, 3-, 6-, and 12-month follow-up. Radiographic changes of hand/wrist at baseline and month 12 were assessed with the Sharp/van der Heijde-modified Sharp score (mTSS). HBV in synovium was determined by immunohistochemical staining for hepatitis B virus surface antigen and hepatitis B virus core antigen (HBcAg) and by nested PCR for the HBV S gene.
RESULTS: HBcAg was found in the synovium of patients with RA with CHB (7 of 11, 64%), which was confirmed by PCR for the HBV S gene. Compared with the non-CHB group, more CD68-positive macrophages, CD20-positive B cells, and CD15-positive neutrophils infiltrated the synovium in the CHB group (all p < 0.05). There were smaller improvements from baseline in most disease activity indicators mainly at month 12, and a significantly higher percentage of CHB patients experienced 1-year radiographic progression (ΔmTSS ≥ 0.5 unit/yr, 64% vs. 26%, p = 0.024). Multivariate logistic regression analysis showed that CHB status (OR 14.230, 95% CI 2.213-95.388; p = 0.006) and the density of synovial CD68-positive macrophages (OR 1.002, 95% CI 1.001-1.003; p = 0.003) were independently associated with 1-year radiographic progression.
CONCLUSIONS:
The presence of HBV in RA synovium may be involved in the pathogenesis of local lesions and exacerbate disease progression in RA.
2020-05-11T14:46:10Z
2020-05-11T14:46:10Z
2018-06-19
Article
Other
Arthritis Res Ther. 2018 Jun 19;20(1):130. doi: 10.1186/s13075-018-1623-y.
29921328
10.1186/s13075-018-1623-y
http://hdl.handle.net/10033/622254
1478-6362
Arthritis research & therapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BMC
20
1
130
Arthritis research & therapy
England
oai:repository.helmholtz-hzi.de:10033/6222572020-05-13T11:39:03Zcom_10033_620601col_10033_620603
2020-05-12T09:36:15Z
urn:hdl:10033/622257
Human Lentiviral Gene Therapy Restores the Cellular Phenotype of Autosomal Recessive Complete IFN-γR1 Deficiency.
Hahn, Katharina
Pollmann, Liart
Nowak, Juliette
Nguyen, Ariane Hai Ha
Haake, Kathrin
Neehus, Anna-Lena
Waqas, Syed F Hassnain
Pessler, Frank
Baumann, Ulrich
Hetzel, Miriam
Casanova, Jean-Laurent
Schulz, Ansgar
Bustamante, Jacinta
Ackermann, Mania
Lachmann, Nico
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Gene Therapy
IFN-γR1 deficiency
Lentiviral Vectors
MSMD
Autosomal recessive (AR) complete interferon-γ receptor 1 (IFN-γR1) deficiency, also known as one genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD), is a life-threatening congenital disease leading to premature death. Affected patients present a pathognomonic predisposition to recurrent and severe infections with environmental mycobacteria or the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine. Current therapeutic options are limited to antibiotic treatment and hematopoietic stem cell transplantation, however with poor outcome. Given the clinical success of gene therapy, we introduce the first lentiviral-based gene therapy approach to restore expression and function of the human IFN-γR-downstream signaling cascade. In our study, we developed lentiviral vectors constitutively expressing the human IFN-γR1 and demonstrate stable transgene expression without interference with cell viability and proliferation in transduced human hematopoietic cells. Using an IFN-γR1-deficient HeLa cell model, we show stable receptor reconstitution and restored IFN-γR1 signaling without adverse effect on cell functionality. Transduction of both SV40-immortalized and primary fibroblasts derived from IFN-γR1-deficient MSMD patients was able to recover IFN-γR1 expression and restore type II IFN signaling upon stimulation with IFN-γ. In summary, we highlight lentiviral vectors to correct the IFN-γ mediated immunity and present the first gene therapy approach for patients suffering from AR complete IFN-γR1 deficiency.
2020-05-12T09:36:15Z
2020-05-12T09:36:15Z
2020-04-11
2020-05-12
Article
Mol Ther Methods Clin Dev. 2020 Apr 11;17:785-795. doi: 10.1016/j.omtm.2020.04.002. eCollection 2020 Jun 12.
2329-0501
32355867
10.1016/j.omtm.2020.04.002
http://hdl.handle.net/10033/622257
Molecular therapy. Methods & clinical development
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier(Cell Press)
17
785
795
Molecular therapy. Methods & clinical development
United States
oai:repository.helmholtz-hzi.de:10033/6224232020-09-03T03:10:04Zcom_10033_620601col_10033_620603
2020-09-02T12:37:12Z
urn:hdl:10033/622423
Impact of Physical Exercise on Gut Microbiome, Inflammation, and the Pathobiology of Metabolic Disorders.
Sohail, Muhammad U
Yassine, Hadi M
Sohail, Aaqib
Al Thani, Asmaa A
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Background: The gastrointestinal tract (GIT) harbors a complex and diverse microbial composition that outnumbers our own body cells and their gene contents. These microbes play a significant role in host metabolism and energy homeostasis. Emerging evidence suggests that the GIT microbiome significantly contributes to host health and that impairments in the microbiome may cause the development of metabolic diseases. The microbiome architecture is shaped by several genetic and environmental factors, including nutrition and physical activity. Physical exercise has preventive or therapeutic effects in respiratory, cardiovascular, neuroendocrine, and muscular diseases. Yet, we still have little information of the beneficial effects of physical exercise on GIT health and microbial composition. Furthermore, we are not aware whether exercise-derived benefits on microbiome diversity can beneficially influence other tissues and body organs.
Objectives: The aim of this article is to review the available literature on exercise-induced microbiome changes and to explain how these changes may induce inflammatory, immune, and oxidative responses that may contribute to the improvement of metabolic disorders.
Methods: A systemic and comprehensive search of the relevant literature using MEDLINE and Google Scholar databases was conducted during fall 2018 and spring 2019. The search identified sixty-two research and review articles that discussed exercise-induced microbiome changes.
Results: The review of the relevant literature suggests that exercise-induced microbial changes affect the host's immune pathways and improve energy homeostasis. Microbes release certain neuroendocrine and immune-modulatory factors that may lower inflammatory and oxidative stress and relieve patients suffering from metabolic disorders.
Conclusions: Exercise-induced changes in microbial diversity are able to improve tissue metabolism, cardiorespiratory fitness, and insulin resistance.
2020-09-02T12:37:12Z
2020-09-02T12:37:12Z
2019-08-04
Review
Other
Rev Diabet Stud. 2019;15:35-48. doi:10.1900/RDS.2019.15.35.
31380886
10.1900/RDS.2019.15.35
http://hdl.handle.net/10033/622423
1614-0575
The review of diabetic studies : RDS
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Society for Biomedical Diabetes Research
15
35
48
The review of diabetic studies : RDS
Singapore
oai:repository.helmholtz-hzi.de:10033/6226482020-12-12T10:31:18Zcom_10033_620601col_10033_620603
2020-12-11T14:38:57Z
urn:hdl:10033/622648
Targeted metabolomic profiling of cerebrospinal fluid from patients with progressive multifocal leukoencephalopathy.
Luo, Yi
Möhn, Nora
Al-Mekhlafi, Amani
Schuchardt, Sven
Skripuletz, Thomas
Sühs, Wolfram
Pessler, Frank
Stangel, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus, is a demyelinating disease of the central nervous system that primarily affects oligodendrocytes. It can cause significant morbidity and mortality. An early diagnosis is of high relevance as timely immune reconstitution is essential. However, diagnosis can be challenging if virus detection via cerebrospinal fluid (CSF) PCR remains negative. Hence, identifying CSF biomarkers for this disease is of crucial importance. We applied a targeted metabolomic screen to CSF from 23 PML patients and eight normal pressure hydrocephalus (NPH) patients as controls. Out of 188 potentially detectable metabolites, 48 (13 amino acids, 4 biogenic amines, 1 acylcarnitine, 21 phosphatidylcholines, 8 sphingolipids, and the sum of hexoses) passed the quality screen and were included in the analyses. Even though there was a tendency towards lower concentrations in PML (mostly of phosphatidylcholines and sphingomyelins), none of the differences between PML and controls in individual metabolite concentrations reached statistical significance (lowest p = 0.104) and there were no potential diagnostic biomarkers (highest area under the ROC curve 0.68). Thus, CSF metabolite changes in PML are likely subtle and possibly larger group sizes and broader metabolite screens are needed to identify potential CSF metabolite biomarkers for PML.
2020-12-11T14:38:57Z
2020-12-11T14:38:57Z
2020-11-24
Article
PLoS One. 2020 Nov 24;15(11):e0242321. doi: 10.1371/journal.pone.0242321.
33232337
10.1371/journal.pone.0242321
http://hdl.handle.net/10033/622648
1932-6203
PloS one
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
PLOS
15
11
e0242321
PloS one
United States
oai:repository.helmholtz-hzi.de:10033/6226852021-01-16T01:44:42Zcom_10033_620601col_10033_620603
2021-01-15T14:52:39Z
urn:hdl:10033/622685
Generation of two human ISG15 knockout iPSC clones using CRISPR/Cas9 editing.
Merkert, S
Jaboreck, M-C
Engels, L
Malik, M N H
Göhring, G
Pessler, F
Martin, U
Olmer, R
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Background and aims: T cells are the main mediators of allogeneic immune responses. Specific T cell clones can be tracked by their unique T cell receptor (TCR), but specificity and function remain elusive and have not been investigated in human liver biopsies thus far.
Methods: TCR repertoire analysis of CD4+, CD8+ and regulatory T cells of the peripheral blood and liver graft was performed in seven liver transplant recipients with either stable course (non-rejector, NR), subclinical cellular rejection (SCR) or acute cellular rejection (ACR) during an observation period from pre-transplant to six years post-transplant. Furthermore, donor-reactive T cells, identified by their expression of CD154 and GARP after allogeneic activation, were tracked longitudinally in peripheral blood and within the liver allograft.
Results: While overall clonality of the TCR repertoire did not increase in peripheral blood after liver transplantation, clonality of donor-reactive CD4+ and regulatory T cells increased and these clones accumulated within the liver graft. Surprisingly, the TCR repertoires between the liver graft and the periphery were distinct and showed only little overlap. Notably, during ACR TCR repertoires aligned suggesting either graft-specific homing or release of activated T cells from the graft.
Conclusions: This is the first study comparing TCR repertoires between liver graft and blood in patients with NR, SCR and ACR. Moreover, we attribute specificity and function to a subgroup of intragraft T cell populations. Given the little overlap between peripheral blood and intragraft repertoires future studies investigating function and specificities of T cells after liver transplantation should focus on the intragraft immune response. For this purpose, protocol biopsies of patients with normal graft function and subclinical rejection have to be taken into account.
2021-01-15T14:52:39Z
2021-01-15T14:52:39Z
2020-12-22
Article
Stem Cell Res. 2020 Dec 22;50:102135. doi: 10.1016/j.scr.2020.102135. Epub ahead of print.
33383405
10.1016/j.scr.2020.102135
http://hdl.handle.net/10033/622685
1876-7753
Stem cell research
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Elsevier
50
102135
Stem cell research
England
oai:repository.helmholtz-hzi.de:10033/6228742021-05-18T01:59:55Zcom_10033_620601col_10033_620603
2021-05-17T12:21:04Z
urn:hdl:10033/622874
Establishment, Validation, and Initial Application of a Sensitive LC-MS/MS Assay for Quantification of the Naturally Occurring Isomers Itaconate, Mesaconate, and Citraconate.
Winterhoff, Moritz
Chen, Fangfang
Sahini, Nishika
Ebensen, Thomas
Kuhn, Maike
Kaever, Volkhard
Bähre, Heike
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CAD
Irg1
Krebs cycle
biomarker
cis-aconitate decarboxylase
citraconate
itaconate
mass spectrometry
mesaconate
metabolism
Itaconate is derived from the tricarboxylic acid (TCA) cycle intermediate cis-aconitate and links innate immunity and metabolism. Its synthesis is altered in inflammation-related disorders and it therefore has potential as clinical biomarker. Mesaconate and citraconate are naturally occurring isomers of itaconate that have been linked to metabolic disorders, but their functional relationships with itaconate are unknown. We aimed to establish a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the quantification of itaconate, mesaconate, citraconate, the pro-drug 4-octyl-itaconate, and selected TCA intermediates. The assay was validated for itaconate, mesaconate, and citraconate for intra- and interday precision and accuracy, extended stability, recovery, freeze/thaw cycles, and carry-over. The lower limit of quantification was 0.098 µM for itaconate and mesaconate and 0.049 µM for citraconate in 50 µL samples. In spike-in experiments, itaconate remained stable in human plasma and whole blood for 24 and 8 h, respectively, whereas spiked-in citraconate and mesaconate concentrations changed during incubation. The type of anticoagulant in blood collection tubes affected measured levels of selected TCA intermediates. Human plasma may contain citraconate (0.4-0.6 µM, depending on the donor), but not itaconate or mesaconate, and lipopolysaccharide stimulation of whole blood induced only itaconate. Concentrations of the three isomers differed greatly among mouse organs: Itaconate and citraconate were most abundant in lymph nodes, mesaconate in kidneys, and only citraconate occurred in brain. This assay should prove useful to quantify itaconate isomers in biomarker and pharmacokinetic studies, while providing internal controls for their effects on metabolism by allowing quantification of TCA intermediates.
2021-05-17T12:21:04Z
2021-05-17T12:21:04Z
2021-04-26
Article
Metabolites. 2021 Apr 26;11(5):270. doi: 10.3390/metabo11050270.
2218-1989
33925995
10.3390/metabo11050270
http://hdl.handle.net/10033/622874
Metabolites
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
11
5
Metabolites
Switzerland
oai:repository.helmholtz-hzi.de:10033/6229452021-07-20T01:41:11Zcom_10033_311308com_10033_620601col_10033_620721col_10033_620603
2021-07-19T15:03:01Z
urn:hdl:10033/622945
Elevated Free Phosphatidylcholine Levels in Cerebrospinal Fluid Distinguish Bacterial from Viral CNS Infections.
Al-Mekhlafi, Amani
Sühs, Kurt-Wolfram
Schuchardt, Sven
Kuhn, Maike
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Klawonn, Frank
Stangel, Martin
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
biomarker
cell membrane
central nervous system
enterovirus
herpes simplex virus
infection
meningitis
metabolism
varicella zoster virus
The identification of CSF biomarkers for bacterial meningitis can potentially improve diagnosis and understanding of pathogenesis, and the differentiation from viral CNS infections is of particular clinical importance. Considering that substantial changes in CSF metabolites in CNS infections have recently been demonstrated, we compared concentrations of 188 metabolites in CSF samples from patients with bacterial meningitis (n = 32), viral meningitis/encephalitis (n = 34), and noninflamed controls (n = 66). Metabolite reprogramming in bacterial meningitis was greatest among phosphatidylcholines, and concentrations of all 54 phosphatidylcholines were significantly (p = 1.2 × 10-25-1.5 × 10-4) higher than in controls. Indeed, all biomarkers for bacterial meningitis vs. viral meningitis/encephalitis with an AUC ≥ 0.86 (ROC curve analysis) were phosphatidylcholines. Four of the five most accurate (AUC ≥ 0.9) phosphatidylcholine biomarkers had higher sensitivity and negative predictive values than CSF lactate or cell count. Concentrations of the 10 most accurate phosphatidylcholine biomarkers were lower in meningitis due to opportunistic pathogens than in meningitis due to typical meningitis pathogens, and they correlated most strongly with parameters reflecting blood-CSF barrier dysfunction and CSF lactate (r = 0.73-0.82), less so with CSF cell count, and not with blood CRP. In contrast to the elevated phosphatidylcholine concentrations in CSF, serum concentrations remained relatively unchanged. Taken together, these results suggest that increased free CSF phosphatidylcholines are sensitive biomarkers for bacterial meningitis and do not merely reflect inflammation but are associated with local disease and a shift in CNS metabolism.
2021-07-19T15:03:01Z
2021-07-19T15:03:01Z
2021-05-06
Article
Cells. 2021 May 6;10(5):1115. doi: 10.3390/cells10051115. PMID: 34066349.
34066349
10.3390/cells10051115
http://hdl.handle.net/10033/622945
2073-4409
Cells
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
10
5
Cells
Switzerland
oai:repository.helmholtz-hzi.de:10033/6231082021-12-02T01:59:58Zcom_10033_620601col_10033_620603
2021-12-01T14:09:08Z
urn:hdl:10033/623108
Transcriptomic Biomarkers for Tuberculosis: Validation of as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response.
de Araujo, Leonardo S
Ribeiro-Alves, Marcelo
Wipperman, Matthew F
Vorkas, Charles Kyriakos
Pessler, Frank
Saad, Maria Helena Féres
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Mycobacterium tuberculosis
NPC2
Niemann–Pick disease type C2
RNA
biomarkers
diagnosis
mRNA
transcription
treatment
tuberculosis
External validation in different cohorts is a key step in the translational development of new biomarkers. We previously described three host mRNA whose expression in peripheral blood is significantly higher (NPC2) or lower (DOCK9 and EPHA4) in individuals with TB compared to latent TB infection (LTBI) and controls. We have now conducted an independent validation of these genes by re-analyzing publicly available transcriptomic datasets from Brazil, China, Haiti, India, South Africa, and the United Kingdom. Comparisons between TB and control/LTBI showed significant differential expression of all three genes (NPC2high p < 0.01, DOCK9low p < 0.01, and EPHA4low p < 0.05). NPC2high had the highest mean area under the ROC curve (AUROC) for the differentiation of TB vs. controls (0.95) and LTBI (0.94). In addition, NPC2 accurately distinguished TB from the clinically similar conditions pneumonia (AUROC, 0.88), non-active sarcoidosis (0.87), and lung cancer (0.86), but not from active sarcoidosis (0.66). Interestingly, individuals progressing from LTBI to TB showed a constant increase in NPC2 expression with time when compared to non-progressors (p < 0.05), with a significant change closer to manifestation of active disease (≤3 months, p = 0.003). Moreover, NPC2 expression normalized with completion of anti-TB treatment. Taken together, these results validate NPC2 mRNA as a diagnostic host biomarker for active TB independent of host genetic background. Moreover, they reveal its potential to predict progression from latent to active infection and to indicate a response to anti-TB treatment.
2021-12-01T14:09:08Z
2021-12-01T14:09:08Z
2021-10-09
Article
Cells. 2021 Oct 9;10(10):2704. doi: 10.3390/cells10102704.
34685683
10.3390/cells10102704
http://hdl.handle.net/10033/623108
2073-4409
Cells
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
10
10
Cells
Switzerland
oai:repository.helmholtz-hzi.de:10033/6231362022-01-12T01:50:58Zcom_10033_620589com_10033_620601com_10033_338554com_10033_620636col_10033_621787col_10033_620603col_10033_620590col_10033_620638
2022-01-11T11:36:56Z
urn:hdl:10033/623136
Congenital deficiency reveals critical role of ISG15 in skin homeostasis.
Malik, Muhammad Nasir Hayat
Waqas, Syed F Hassnain
Zeitvogel, Jana
Cheng, Jingyuan
Geffers, Robert
Gouda, Zeinab Abu-Elbaha
Elsaman, Ahmed Mahrous
Radwan, Ahmed R
Schefzyk, Matthias
Braubach, Peter
Auber, Bernd
Olmer, Ruth
Müsken, Mathias
Roesner, Lennart M
Gerold, Gisa
Schuchardt, Sven
Merkert, Sylvia
Martin, Ulrich
Meissner, Felix
Werfel, Thomas
Pessler, Frank
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Autoimmunity
Collagens
Monogenic diseases
Skin
Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-β1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.
2022-01-11T11:36:56Z
2022-01-11T11:36:56Z
2021-11-30
Article
J Clin Invest. 2021 Nov 30:e141573. doi: 10.1172/JCI141573. Epub ahead of print.
34847081
10.1172/JCI141573
http://hdl.handle.net/10033/623136
1558-8238
The Journal of clinical investigation
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Society of clinical investigation
The Journal of clinical investigation
United States
oai:repository.helmholtz-hzi.de:10033/6231642022-02-16T02:00:10Zcom_10033_620626com_10033_620652com_10033_620601com_10033_620636col_10033_620666col_10033_620627col_10033_620629col_10033_620603col_10033_620638col_10033_620637
2022-02-15T09:24:24Z
urn:hdl:10033/623164
Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.
Sohail, Aaqib
Iqbal, Azeem A
Sahini, Nishika
Chen, Fangfang
Tantawy, Mohamed
Waqas, Fakhar
Winterhoff, Moritz
Ebensen, Thomas
Schultz, Kristin
Geffers, Robert
Schughart, Klaus
Preusse, Matthias
Shehata, Mahmoud
Bähre, Heike
Pils, Marina C
Guzman, Carlos A
Mostafa, Ahmed
Pleschka, Stephan
Falk, Christine
Michelucci, Alessandro
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. Itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.
2022-02-15T09:24:24Z
2022-02-15T09:24:24Z
2022-01-13
Article
PLoS Pathog. 2022 Jan 13;18(1):e1010219. doi: 10.1371/journal.ppat.1010219. Epub ahead of print.
35025971
10.1371/journal.ppat.1010219
http://hdl.handle.net/10033/623164
1553-7374
PLoS pathogens
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
PLOS
18
1
e1010219
PLoS pathogens
United States