group leader: Pessler

Recent Submissions

  • 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. (2017-10-30)
    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),
  • 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. (2018-01-01)
    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
  • 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.
    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.
  • 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. (2018-05-08)
    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.
  • 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. (2018-01-17)
    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.
  • 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. (2018-01-24)
    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.
  • 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. (2017-03)
    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.
  • 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. (2017-03-01)
    To examine the impact of hepatitis B vaccination schedules and types of vaccines on hepatitis B vaccination timing.
  • 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. (2017-10-30)
  • Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection.

    Preusse, Matthias; Schughart, Klaus; Pessler, Frank (2017)
    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.
  • 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. (2017-06-06)
    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.
  • 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 (2011-02-01)
    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.
  • 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. (2017-05-12)
    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.
  • 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. (2017-02-02)
    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.
  • 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; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017)
    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).
  • 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. (2017-02-21)
    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.
  • 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 (2013-05-30)
    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.
  • 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 (2013-12-17)
    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.
  • 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. (2016)
    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.
  • 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 (2016-09)
    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.

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