group leader: Dr. Strowig

Recent Submissions

  • Successful Fecal Microbiota Transplantation in a Patient with Severe Complicated Clostridium difficile Infection after Liver Transplantation.

    Schneider, Kai Markus; Wirtz, Theresa H; Kroy, Daniela; Albers, Stefanie; Neumann, Ulf Peter; Strowig, Till; Sellge, Gernot; Trautwein, Christian; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-18)
    Clostridium difficile infection (CDI) represents one of the most common healthcare-associated infections. Due to increasing numbers of recurrences and therapy failures, CDI has become a major disease burden. Studies have shown that fecal microbiota transplantation (FMT) can both be a safe and highly efficacious therapy for patients with therapy-refractory CDI. However, patients undergoing solid organ transplantation are at high risk for CDI due to long-term immunosuppression, previous antibiotic therapy, and proton pump inhibitor use. Additionally, these patients may be especially prone to adverse events related to FMT. Here, we report a successful FMT in a patient with severe therapy-refractory CDI after liver transplantation.
  • Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency.

    Heine, Wiebke; Beckstette, Michael; Heroven, Ann Kathrin; Thiemann, Sophie; Heise, Ulrike; Nuss, Aaron Mischa; Pisano, Fabio; Strowig, Till; Dersch, Petra; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02)
    Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style.
  • The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.

    Hu, Bo; Jin, Chengcheng; Li, Hua-Bing; Tong, Jiyu; Ouyang, Xinshou; Cetinbas, Naniye Malli; Zhu, Shu; Strowig, Till; Lam, Fred C; Zhao, Chen; Henao-Mejia, Jorge; Yilmaz, Omer; Fitzgerald, Katherine A; Eisenbarth, Stephanie C; Elinav, Eran; Flavell, Richard A; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
    Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.
  • Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells.

    Roy, Urmi; Gálvez, Eric J C; Iljazovic, Aida; Lesker, Till Robin; Błażejewski, Adrian J; Pils, Marina C; Heise, Ulrike; Huber, Samuel; Flavell, Richard A; Strowig, Till; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-10-24)
    Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4+ T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures.
  • Shaping of Intestinal Microbiota in Nlrp6- and Rag2-Deficient Mice Depends on Community Structure.

    Gálvez, Eric J C; Iljazovic, Aida; Gronow, Achim; Flavell, Richard; Strowig, Till; Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017-12-26)
    Contradicting observations have been made regarding the relative contributions of immune sensors to shaping the microbiome, yet the reasons for these discrepancies are not fully understood. Here, we investigated the contribution of environmental factors in shaping the microbiome in mice deficient in adaptive immunity (Rag2-/-) and Nlrp6, an immune sensor proposed to be involved in regulation of microbiota composition. In conventionally housed Nlrp6-/- mice, familial transmission has a significant effect on microbiota composition, complicating the analysis of genotype-dependent effects. Notably, after rederivation into standardized specific pathogen-free (SPF) conditions devoid of pathobionts, microbiota composition was indistinguishable between WT, Rag2-/-, and Nlrp6-/- mice. However, upon reintroduction of a pathobiont-containing community host, genotype-dependent differences reappear, specifically affecting the relative abundance of pathobionts such as Helicobacter spp. Our results show that the impact of Nlrp6 and also of adaptive immunity on microbiota composition depends on community structure and primarily influences pathobionts but not commensals.
  • Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss.

    Lucas, Sébastien; Omata, Yasunori; Hofmann, Jörg; Böttcher, Martin; Iljazovic, Aida; Sarter, Kerstin; Albrecht, Olivia; Schulz, Oscar; Krishnacoumar, Brenda; Krönke, Gerhard; Herrmann, Martin; Mougiakakos, Dimitrios; Strowig, Till; Schett, Georg; Zaiss, Mario M; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018)
    Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.
  • A flagellum-specific chaperone facilitates assembly of the core type III export apparatus of the bacterial flagellum.

    Fabiani, Florian D; Renault, Thibaud T; Peters, Britta; Dietsche, Tobias; Gálvez, Eric J C; Guse, Alina; Freier, Karen; Charpentier, Emmanuelle; Strowig, Till; Franz-Wachtel, Mirita; Macek, Boris; Wagner, Samuel; Hensel, Michael; Erhardt, Marc; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-08)
    Many bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP-FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery.
  • Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.

    Błażejewski, Adrian J; Thiemann, Sophie; Schenk, Alexander; Pils, Marina C; Gálvez, Eric J C; Roy, Urmi; Heise, Ulrike; de Zoete, Marcel R; Flavell, Richard A; Strowig, Till; Helmholtz Centre for infection research, Inhoffenstr. 7. 38124 Braunschweig, Germany. (2017-06-13)
    Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1(-/-) and Casp11(-/-) mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1(-/-) mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.
  • MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium.

    Friedrich, Christin; Mamareli, Panagiota; Thiemann, Sophie; Kruse, Friederike; Wang, Zuobai; Holzmann, Bernhard; Strowig, Till; Sparwasser, Tim; Lochner, Matthias; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str.7, 30625 Hannover, Germany. (2017-05)
    MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.
  • Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities.

    Rausch, Philipp; Basic, Marijana; Batra, Arvind; Bischoff, Stephan C; Blaut, Michael; Clavel, Thomas; Gläsner, Joachim; Gopalakrishnan, Shreya; Grassl, Guntram A; Günther, Claudia; Haller, Dirk; Hirose, Misa; Ibrahim, Saleh; Loh, Gunnar; Mattner, Jochen; Nagel, Stefan; Pabst, Oliver; Schmidt, Franziska; Siegmund, Britta; Strowig, Till; Volynets, Valentina; Wirtz, Stefan; Zeissig, Sebastian; Zeissig, Yvonne; Bleich, André; Baines, John F; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-08)
    The intestinal microbiota is involved in many physiological processes and it is increasingly recognized that differences in community composition can influence the outcome of a variety of murine models used in biomedical research. In an effort to describe and account for the variation in intestinal microbiota composition across the animal facilities of participating members of the DFG Priority Program 1656 "Intestinal Microbiota", we performed a survey of C57BL/6J mice from 21 different mouse rooms/facilities located at 13 different institutions across Germany. Fresh feces was sampled from five mice per room/facility using standardized procedures, followed by extraction and 16S rRNA gene profiling (V1-V2 region, Illumina MiSeq) at both the DNA and RNA (reverse transcribed to cDNA) level. In order to determine the variables contributing to bacterial community differences, we collected detailed questionnaires of animal husbandry practices and incorporated this information into our analyses. We identified considerable variation in a number of descriptive aspects including the proportions of major phyla, alpha- and beta diversity, all of which displayed significant associations to specific aspects of husbandry. Salient findings include a reduction in alpha diversity with the use of irradiated chow, an increase in inter-individual variability (beta diversity) with respect to barrier access and open cages and an increase in bacterial community divergence with time since importing from a vendor. We further observe a high degree of facility-level individuality, which is likely due to each facility harboring its own unique combination of multiple varying attributes of animal husbandry. While it is important to account and control for such differences between facilities, the documentation of such diversity may also serve as a valuable future resource for investigating the origins of microbial-driven host phenotypes.