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  • Soluble immune markers in the different phases of chronic hepatitis B virus infection

    Wiegand, Steffen B.; Beggel, Bastian; Wranke, Anika; Aliabadi, Elmira; Jaroszewicz, Jerzy; Xu, Cheng Jian; Li, Yang; Manns, Michael P.; Lengauer, Thomas; Wedemeyer, Heiner; et al. (Nature publishing group, 2019-10-01)
    Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-β and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-β and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.
  • Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy.

    Soon, Chai Fen; Zhang, Shihong; Suneetha, Pothakamuri Venkata; Antunes, Dinler Amaral; Manns, Michael Peter; Raha, Solaiman; Schultze-Florey, Christian; Prinz, Immo; Wedemeyer, Heiner; Sällberg Chen, Margaret; et al. (Frontiers, 2019-01-01)
    T cell immunotherapy is a concept developed for the treatment of cancer and infectious diseases, based on cytotoxic T lymphocytes to target tumor- or pathogen-specific antigens. Antigen-specificity of the T cell receptors (TCRs) is an important selection criterion in the developmental design of immunotherapy. However, off-target specificity is a possible autoimmunity concern if the engineered antigen-specific T cells are cross-reacting to self-peptides in-vivo. In our recent work, we identified several hepatitis E virus (HEV)-specific TCRs as potential candidates to be developed into T cell therapy to treat chronic hepatitis E. One of the identified TCRs, targeting a HLA-A2-restricted epitope at the RNA-dependent RNA polymerase (HEV-1527: LLWNTVWNM), possessed a unique multiple glycine motif in the TCR-β CDR3, which might be a factor inducing cross-reactivity. The aim of our study was to explore if this TCR could cross-recognize self-peptides to underlay autoimmunity. Indeed, we found that this HEV-1527-specific TCR could also cross-recognize an apoptosis-related epitope, Nonmuscle Myosin Heavy Chain 9 (MYH9-478: QLFNHTMFI). While this TCR had dual specificities to both viral epitope and a self-antigen by double Dextramer binding, it was selectively functional against HEV-1527 but not activated against MYH9-478. The consecutive glycine motif in β chain may be the reason promoting TCR binding promiscuity to recognize a secondary target, thereby facilitating cross-recognition. In conclusion, candidate TCRs for immunotherapy development should be screened for autoimmune potential, especially when the TCRs exhibit unique sequence pattern.
  • Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies

    Pesarrodona, Mireia; Jauset, Toni; Díaz-Riascos, Zamira V.; Sánchez-Chardi, Alejandro; Beaulieu, Marie Eve; Seras-Franzoso, Joaquin; Sánchez-García, Laura; Baltà-Foix, Ricardo; Mancilla, Sandra; Fernández, Yolanda; et al. (Wiley-VCH, 2019-01-01)
    Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44+ tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins
  • Catalytically Active Cas9 Mediates Transcriptional Interference to Facilitate Bacterial Virulence.

    Ratner, Hannah K; Escalera-Maurer, Andrés; Le Rhun, Anaïs; Jaggavarapu, Siddharth; Wozniak, Jessie E; Crispell, Emily K; Charpentier, Emmanuelle; Weiss, David S; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier; Cell Press, 2019-06-24)
    In addition to defense against foreign DNA, the CRISPR-Cas9 system of Francisella novicida represses expression of an endogenous immunostimulatory lipoprotein. We investigated the specificity and molecular mechanism of this regulation, demonstrating that Cas9 controls a highly specific regulon of four genes that must be repressed for bacterial virulence. Regulation occurs through a protospacer adjacent motif (PAM)-dependent interaction of Cas9 with its endogenous DNA targets, dependent on a non-canonical small RNA (scaRNA) and tracrRNA. The limited complementarity between scaRNA and the endogenous DNA targets precludes cleavage, highlighting the evolution of scaRNA to repress transcription without lethally targeting the chromosome. We show that scaRNA can be reprogrammed to repress other genes, and with engineered, extended complementarity to an exogenous target, the repurposed scaRNA:tracrRNA-FnoCas9 machinery can also direct DNA cleavage. Natural Cas9 transcriptional interference likely represents a broad paradigm of regulatory functionality, which is potentially critical to the physiology of numerous Cas9-encoding pathogenic and commensal organisms.
  • Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection.

    Marcellin, Patrick; Wong, Dave; Sievert, William; Buggisch, Peter; Petersen, Jörg; Flisiak, Robert; Manns, Michael; Kaita, Kelly; Krastev, Zahari; Lee, Samuel S; et al. (Wiley-Blackwell, 2019-05-28)
    Background & Aims Tenofovir disoproxil fumarate (TDF) is a first‐line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well‐described cohort of CHB patients. Methods Hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients from two randomised, double‐blind trials (ClinicalTrials. gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open‐label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety, and tolerability. Results Of 641 randomised and treated patients, 585 (91%) entered the open‐label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg‐negative patients and 78/80 (98%) of HBeAg‐positive patients with available data achieved hepatitis B virus (HBV) DNA <69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal‐ or bone‐related adverse events. Conclusions Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.
  • miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.

    Łyszkiewicz, Marcin; Winter, Samantha J; Witzlau, Katrin; Föhse, Lisa; Brownlie, Rebecca; Puchałka, Jacek; Verheyden, Nikita A; Kunze-Schumacher, Heike; Imelmann, Esther; Blume, Jonas; et al. (PLOS, 2019-03-01)
    The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
  • A Listeria monocytogenes ST2 clone lacking chitinase ChiB from an outbreak of non-invasive gastroenteritis.

    Halbedel, Sven; Prager, Rita; Banerji, Sangeeta; Kleta, Sylvia; Trost, Eva; Nishanth, Gopala; Alles, Georg; Hölzel, Christina; Schlesiger, Friederike; Pietzka, Ariane; et al. (Springer Nature, 2019-01-01)
    An outbreak with a remarkable Listeria monocytogenes clone causing 163 cases of non-invasive listeriosis occurred in Germany in 2015. Core genome multi locus sequence typing grouped non-invasive outbreak isolates and isolates obtained from related food samples into a single cluster, but clearly separated genetically close isolates obtained from invasive listeriosis cases. A comparative genomic approach identified a premature stop codon in the chiB gene, encoding one of the two L. monocytogenes chitinases, which clustered with disease outcome. Correction of this premature stop codon in one representative gastroenteritis outbreak isolate restored chitinase production, but effects in infection experiments were not found. While the exact role of chitinases in virulence of L. monocytogenes is still not fully understood, our results now clearly show that ChiB-derived activity is not required to establish L. monocytogenes gastroenteritis in humans. This limits a possible role of ChiB in human listeriosis to later steps of the infection.
  • Virulence of Agrobacterium tumefaciens requires lipid homeostasis mediated by the lysyl-phosphatidylglycerol hydrolase AcvB.

    Groenewold, Maike K; Hebecker, Stefanie; Fritz, Christiane; Czolkoss, Simon; Wiesselmann, Milan; Heinz, Dirk W; Jahn, Dieter; Narberhaus, Franz; Aktas, Meriyem; Moser, Jürgen; et al. (Wiley-Blackwell, 2019-01-01)
    Agrobacterium tumefaciens transfers oncogenic T-DNA via the type IV secretion system (T4SS) into plants causing tumor formation. The acvB gene encodes a virulence factor of unknown function required for plant transformation. Here we specify AcvB as a periplasmic lysyl-phosphatidylglycerol (L-PG) hydrolase, which modulates L-PG homeostasis. Through functional characterization of recombinant AcvB variants, we showed that the C-terminal domain of AcvB (residues 232-456) is sufficient for full enzymatic activity and defined key residues for catalysis. Absence of the hydrolase resulted in ~10-fold increase in L-PG in Agrobacterium membranes and abolished T-DNA transfer and tumor formation. Overproduction of the L-PG synthase gene (lpiA) in wild-type A. tumefaciens resulted in a similar increase in the L-PG content (~7-fold) and a virulence defect even in the presence of intact AcvB. These results suggest that elevated L-PG amounts (either by overproduction of the synthase or absence of the hydrolase) are responsible for the virulence phenotype. Gradually increasing the L-PG content by complementation with different acvB variants revealed that cellular L-PG levels above 3% of total phospholipids interfere with T-DNA transfer. Cumulatively, this study identified AcvB as a novel virulence factor required for membrane lipid homeostasis and T-DNA transfer.
  • Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis.

    Tsay, Hsin-Chieh; Yuan, Qinggong; Balakrishnan, Asha; Kaiser, Marina; Möbus, Selina; Kozdrowska, Emilia; Farid, Marwa; Tegtmeyer, Pia-Katharina; Borst, Katharina; Vondran, Florian W R; et al. (Elsevier, 2018-12-22)
    Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive. Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis. Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.
  • Guidelines for Small-Scale Production and Purification of Hepatitis B Surface Antigen Virus-Like Particles from Recombinant Pichia pastoris.

    Zahid, Maria; Rinas, Ursula; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Humana Press, 2019-01-01)
    Virus-like particle (VLP)-based vaccines have been in the market since decades for preventing viral infection and have proven their usefulness also in other areas of biotechnology. Here, we describe in detail simple small-scale production and purification procedures for the generation of hepatitis B surface antigen (HBsAg) VLPs using Pichia pastoris as expression host. This protocol may also be applicable with variations to other HBsAg-based VLPs additionally carrying antigens of other pathogens.
  • An endothelial cell line infected by Kaposi's sarcoma-associated herpes virus (KSHV) allows the investigation of Kaposi's sarcoma and the validation of novel viral inhibitors in vitro and in vivo.

    Dubich, Tatyana; Lieske, Anna; Santag, Susann; Beauclair, Guillaume; Rückert, Jessica; Herrmann, Jennifer; Gorges, Jan; Büsche, Guntram; Kazmaier, Uli; Hauser, Hansjörg; et al. (2019-01-04)
    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a tumor of endothelial origin predominantly affecting immunosuppressed individuals. Up to date, vaccines and targeted therapies are not available. Screening and identification of anti-viral compounds are compromised by the lack of scalable cell culture systems reflecting properties of virus-transformed cells in patients. Further, the strict specificity of the virus for humans limits the development of in vivo models. In this study, we exploited a conditionally immortalized human endothelial cell line for establishment of in vitro 2D and 3D KSHV latency models and the generation of KS-like xenograft tumors in mice. Importantly, the invasive properties and tumor formation could be completely reverted by purging KSHV from the cells, confirming that tumor formation is dependent on the continued presence of KSHV, rather than being a consequence of irreversible transformation of the infected cells. Upon testing a library of 260 natural metabolites, we selected the compounds that induced viral loss or reduced the invasiveness of infected cells in 2D and 3D endothelial cell culture systems. The efficacy of selected compounds against KSHV-induced tumor formation was verified in the xenograft model. Together, this study shows that the combined use of anti-viral and anti-tumor assays based on the same cell line is predictive for tumor reduction in vivo and therefore allows faithful selection of novel drug candidates against Kaposi's sarcoma. KEY MESSAGES: Novel 2D, 3D, and xenograft mouse models mimic the consequences of KSHV infection. KSHV-induced tumorigenesis can be reverted upon purging the cells from the virus. A 3D invasiveness assay is predictive for tumor reduction in vivo. Chondramid B, epothilone B, and pretubulysin D diminish KS-like lesions in vivo.
  • Macrophage entrapped silica coated superparamagnetic iron oxide particles for controlled drug release in a 3D cancer model.

    Ullah, Sami; Seidel, Katja; Türkkan, Sibel; Warwas, Dawid Peter; Dubich, Tatyana; Rohde, Manfred; Hauser, Hansjörg; Behrens, Peter; Kirschning, Andreas; Köster, Mario; et al. (2018-12-23)
    Targeted delivery of drugs is a major challenge in treatment of diverse diseases. Systemically administered drugs demand high doses and are accompanied by poor selectivity and side effects on non-target cells. Here, we introduce a new principle for targeted drug delivery. It is based on macrophages as transporters for nanoparticle-coupled drugs as well as controlled release of drugs by hyperthermia mediated disruption of the cargo cells and simultaneous deliberation of nanoparticle-linked drugs. Hyperthermia is induced by an alternating electromagnetic field (AMF) that induces heat from silica-coated superparamagnetic iron oxide nanoparticles (SPIONs). We show proof-of-principle of controlled release by the simultaneous disruption of the cargo cells and the controlled, AMF induced release of a toxin, which was covalently linked to silica-coated SPIONs via a thermo-sensitive linker. Cells that had not been loaded with SPIONs remain unaffected. Moreover, in a 3D co-culture model we demonstrate specific killing of associated tumour cells when employing a ratio as low as 1:40 (SPION-loaded macrophage: tumour cells). Overall, our results demonstrate that AMF induced drug release from macrophage-entrapped nanoparticles is tightly controlled and may be an attractive novel strategy for targeted drug release.
  • Developmental induction of human T-cell responses against Candida albicans and Aspergillus fumigatus.

    Vogel, Katrin; Pierau, Mandy; Arra, Aditya; Lampe, Karen; Schlueter, Dirk; Arens, Christoph; Brunner-Weinzierl, Monika C; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Nature publishing group, 2018-11-15)
    The origin of human T-cell responses against fungal pathogens early in life is not clearly understood. Here, we show that antifungal T-cell responses are vigorously initiated within the first years of life against lysates and peptides of Candida albicans or Aspergillus fumigatus, presented by autologous monocytes. The neonatal responding T-cell pool consists of 20 different TCR-V
  • Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants.

    Khera, Tanvi; Behrendt, Patrick; Bankwitz, Dorothea; Brown, Richard J P; Todt, Daniel; Doepke, Mandy; Ghafoor Khan, Abdul; Schulze, Kai; Law, John; Logan, Michael; et al. (Elsevier, 2018-11-12)
    Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an HCV vaccine. Conserved epitopes like the viral CD81-binding site are targeted by rare broadly neutralizing antibodies. However, these viral segments are occluded by variable regions and glycans. We aimed to identify antigens exposing conserved epitopes and to characterize their immunogenicity. We created HCV variants with mutated glycosylation sites and/or hypervariable region 1 (HVR1). Exposure of the CD81 binding site and conserved epitopes was quantified by soluble CD81 and antibody interaction and neutralization assays. E2 or E1-E2 heterodimers with mutations causing epitope exposure were used to immunize mice. Vaccine-induced antibodies were examined and compared with patient-derived antibodies. Mutant viruses bound soluble CD81 and antibodies targeting the CD81 binding site with enhanced efficacy. Mice immunized with E2 or E1E2 heterodimers incorporating these modifications mounted strong, cross-binding, and non-interfering antibodies. E2-induced antibodies neutralized the autologous virus but they were not cross-neutralizing. Viruses lacking the HVR1 and selected glycosylation sites expose the CD81 binding site and cross-neutralization antibody epitopes. Recombinant E2 proteins carrying these modifications induce strong cross-binding but not cross-neutralizing antibodies.
  • Importance of flagella in acute and chronic Pseudomonas aeruginosa infections.

    Lorenz, Anne; Preuße, Matthias; Bruchmann, Sebastian; Pawar, Vinay; Grahl, Nora; Pils, Marina C; Nolan, Laura M; Filloux, Alain; Weiss, Siegfried; Häussler, Susanne; et al. (Wiley-Blackwell, 2018-11-08)
    Pseudomonas aeruginosa is an environmental microorganism and a causative agent of diverse acute and chronic, biofilm-associated infections. Advancing research-based knowledge on its adaptation to conditions within the human host is bound to reveal novel strategies and targets for therapeutic intervention. Here, we investigated the traits that P. aeruginosa PA14 as well as a virulence attenuated ΔlasR mutant need to survive in selected murine infection models. Experimentally, the genetic programs that the bacteria use to adapt to biofilm-associated versus acute infections were dissected by passaging transposon mutant libraries through mouse lungs (acute) or mouse tumours (biofilm-infection). Adaptive metabolic changes of P. aeruginosa were generally required during both infection processes. Counter-selection against flagella expression was observed during acute lung infections. Obviously, avoidance of flagella-mediated activation of host immunity is advantageous for the wildtype bacteria. For the ΔlasR mutant, loss of flagella did not confer a selective advantage. Apparently, other pathogenesis mechanisms are active in this virulence attenuated strain. In contrast, the infective process of P. aeruginosa in the chronic biofilm model apparently required expression of flagellin. Together, our findings imply that the host immune reactions against the infectious agent are very decisive for acuteness and duration of the infectious disease. They direct disease outcome.
  • Induced B Cell Development in Adult Mice.

    Brennecke, Anne-Margarete; Düber, Sandra; Roy, Bishnudeo; Thomsen, Irene; Garbe, Annette I; Klawonn, Frank; Pabst, Oliver; Kretschmer, Karsten; Weiss, Siegfried; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-01-01)
    We employed the B-Indu-Rag1 model in which the coding exon of recombination-activating gene 1 (Rag1) is inactivated by inversion. It is flanked by inverted loxP sites. Accordingly, B cell development is stopped at the pro/pre B-I cell precursor stage. A B cell-specific Cre recombinase fused to a mutated estrogen receptor allows the induction of RAG1 function and B cell development by application of Tamoxifen. Since Rag1 function is recovered in a non-self-renewing precursor cell, only single waves of development can be induced. Using this system, we could determine that B cells minimally require 5 days to undergo development from pro/preB-I cells to the large and 6 days to the small preB-II cell stage. First immature transitional (T) 1 and T2 B cells could be detected in the bone marrow at day 6 and day 7, respectively, while their appearance in the spleen took one additional day. We also tested a contribution of adult bone marrow to the pool of B-1 cells. Sublethally irradiated syngeneic WT mice were adoptively transferred with bone marrow of B-Indu-Rag1 mice and B cell development was induced after 6 weeks. A significant portion of donor derived B-1 cells could be detected in such adult mice. Finally, early VH gene usage was tested after induction of B cell development. During the earliest time points the VH genes proximal to D/J were found to be predominantly rearranged. At later time points, the large family of the most distal VH prevailed.
  • Autoimmune hepatitis: From the initial therapy to the differentiated approach [Autoimmunhepatitis: Von der ersten Therapie zum differenzierten Vorgehen]

    Taubert, R.; Manns, M. P.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
    Gegliederte Zusammenfassung Hintergrund: Die Autoimmunhepatitis (AIH) ist zwar eine seltene Erkrankung zeigt aber wie andere Autoimmunerkrankungen in der westlichen Welt eine ansteigende Inzidenz und hat unbehandelt einen schlechten natürlichen Verlauf. Ziel der Arbeit (Fragestellung): Darstellung des aktuellen Kenntnisstands zur Pathogenese, Diagnostik und Behandlung der AIH. Material und Methoden: Zusammenfassung der gültigen nationalen sowie internationalen Leitlinien und exemplarischer aktuell publizierter Studien. Ergebnisse und Diskussion: Die Therapie der AIH aus Prednisolon +/- Azathioprin war beginnend in den 1960 Jahren die erste medikamentöse Therapie einer Lebererkrankung, die die Lebenserwartung nachweislich verbessern konnte. Seit 2011 Jahren ist zusätzlich Budesonid für AIH-Patienten ohne Leberzirrhose als alternatives Steroid mit weniger systemischen Nebenwirkungen zugelassen. Abgesehen davon hat sich die initiale Erstlinientherapie der AIH in den letzten 40 Jahren nicht grundlegend verändert. Das Therapieziel der kompletten biochemischen Remission wird bei ca. 70-80% der Patienten erreicht. Bei hohen Rückfallraten trotz lang anhaltender biochemischer und histologischer Remission ist bei den meisten Patienten eine lebenslange Therapie notwendig. Bisherige Zweitlinientherapien beruhen vor allem auf retrospektiven Studienergebnissen und daher fehlen einheitliche Empfehlungen zur Zweitlinientherapie von den internationalen Fachgesellschaften. Ebenso ist keine Zweitlinientherapie von den Zulassungsbehörden wie FDA oder EMA zugelassen.
  • Die nicht-alkoholische Fettlebererkrankung : Die Rolle der Leber im metabolischen Syndrom

    Jupa, K.L.; Manns, M.P.; Jäckel, E; DZIF,Deutsches Zentrum für Infektionsforschung; HZI, Helmholtz-Zentrum für Infektiondforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig.
    Epidemiologie Die nicht-alkoholische Fettlebererkrankung (»non-alcoholic fatty liver disease«, NAFLD) ist mittlerweile eine der häufigsten Lebererkrankung weltweit mit einer mittleren Prävalenz von 20% weltweit und bis zu 30% in Europa [1]. Als Hauptrisikofaktoren gelten einerseits verschiedene Umweltfaktoren, insbesondere Bewegungsmangel und falsche Ernährung sowie andererseits die verschiedenen Aspekte des metabolischen Syndroms: Adipositas, Fettstoffwechselstörungen sowie Insulinresistenz und Diabetes mellitus Typ 2. Aus diesem Grund wird die Fettleber mittlerweile auch als hepatische Komponente des metabolischen Syndroms bezeichnet. Neben den Umweltfaktoren konnte auch gezeigt werden, dass eine genetische Prädisposition im Sinne von einem Adiponutrin Polymorphismus (»patatin-like phospholipase domain containing 3«, PNPLA3 [2, 3] zu einem gehäuften Auftreten einer Fettlebererkrankung führen kann.
  • RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B.

    Broglia, Laura; Materne, Solange; Lécrivain, Anne-Laure; Hahnke, Karin; Le Rhun, Anaïs; Charpentier, Emmanuelle; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-01-01)
    Endoribonuclease Y (RNase Y) is a crucial regulator of virulence in Gram-positive bacteria. In the human pathogen Streptococcus pyogenes, RNase Y is required for the expression of the major secreted virulence factor streptococcal pyrogenic exotoxin B (SpeB), but the mechanism involved in this regulation remains elusive. Here, we demonstrate that the 5' untranslated region of speB mRNA is processed by several RNases including RNase Y. In particular, we identify two RNase Y cleavage sites located downstream of a guanosine (G) residue. To assess whether this nucleotide is required for RNase Y activity in vivo, we mutated it and demonstrate that the presence of this G residue is essential for the processing of the speB mRNA 5' UTR by RNase Y. Although RNase Y directly targets and processes speB, we show that RNase Y-mediated regulation of speB expression occurs primarily at the transcriptional level and independently of the processing in the speB mRNA 5' UTR. To conclude, we demonstrate for the first time that RNase Y processing of an mRNA target requires the presence of a G. We also provide new insights on the speB 5' UTR and on the role of RNase Y in speB regulation.
  • Itaconic acid indicates cellular but not systemic immune system activation.

    Meiser, Johannes; Kraemer, Lisa; Jaeger, Christian; Madry, Henning; Link, Andreas; Lepper, Philipp M; Hiller, Karsten; Schneider, Jochen G; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-08-14)
    Itaconic acid is produced by mammalian leukocytes upon pro-inflammatory activation. It appears to inhibit bacterial growth and to rewire the metabolism of the host cell by inhibiting succinate dehydrogenase. Yet, it is unknown whether itaconic acid acts only intracellularly, locally in a paracrine fashion, or whether it is even secreted from the inflammatory cells at meaningful levels in peripheral blood of patients with severe inflammation or sepsis. The aim of this study was to determine the release rate of itaconic acid from pro-inflammatory activated macrophages

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