INFLACOMM · Interplay of inflammasomes, commensals and pathogens at mucosal interfaces
FP7 — People (Marie Curie Actions)
- Duration
- 2013-10-01 → 2017-09-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Interplay of inflammasomes, commensals and pathogens at mucosal interfaces
Humans are colonized and surrounded by complex microbial ecosystems containing many microbes beneficial to human health, but also ones that are able to cause serious diseases. The host’s innate immune system plays a vital role in the decision-making on whether to combat a specific microbe, i.e. raise an inflammatory response, or whether to ignore them, i.e. maintain a tolerogenic environment. Evidence from numerous studies suggests that dysregulated or impaired innate immune responses are significantly contributing to diseases with significant impact on human health including Inflammatory Bowel Diseases (IBD) and Rheumatoid Arthritis, however the contribution of specific receptors and pathways has only been partially solved. The objectives of the ongoing research funded by the CIG in my “Young Investigator Group” at the Helmholtz Centre for Infection Research is to elucidate the contribution of a specific family of innate receptors, that share the ability to induce formation of so-called inflammasomes, in intestinal homeostasis and inflammation. Inflammasomes are platforms regulating the activity of the protease caspase-1, which controls the release of proinflammatory cytokines and is able to induce a specific form of inflammatory cell death. Conflicting results had been reported regarding their function in intestinal inflammation in mouse models of IBD. Our current results suggest that the outcomes of these experiments are strongly influenced by the composition of the intestinal microbiota and by complex interactions of caspase-1 and a related protease, caspase-11. Funding though CIG has been instrumental in setting up my research group by providing funds to recruit a graduate student and to establish this project, whose interesting results we successfully published (Blazejewski et al, Cell Reports 2017). These results are likely to have a wider impact on how to characterize animal models of complex diseases including, but not limited to, IBD.
Data: CORDIS, © European Union
Project objective
Inflammasomes are multi-protein complexes that control the activity of the cysteine protease caspase-1. Inflammasomes are assembled around one of several different sensor proteins, which enable inflammasome activation after sensing of diverse microbial and endogenous damage-associated molecules. Recently, I discovered a novel role for the NLRP6 inflammasome in regulation of the intestinal microbiota of mice. In its absence an altered microbiota, called dysbiosis, develops that increases the severity of experimentally-induced colitis. Strikingly, transfer of the altered microbiota to WT mice resulted in exacerbated colitis in these mice compared to normal WT mice. These findings highlight two important features of the interplay of host and microbiota. First, that deficiencies in the immune system may lead to pathologic aberrations in the commensal microbiota. In this proposal I will address how the NLRP6 inflammasome regulates the microbiota using newly generated gene-deficient mouse strains as well as germfree mouse models. The second implication is that the microbiota has a large effect on mucosal inflammatory processes that are largely regulated by its specific composition. Dysbiosis is observed in many human individuals with immune-mediated diseases, but its impact on other aspects of immunity is less well characterized. Hence, I intend to study the effects of the microbiota, specifically dysbiosis, on orchestrating anti-microbial immune responses, as well as the impact in host response to vaccination. Specifically, I will study vaccination and challenge models of bacterial and viral pathogens that enter through mucosal routes, i.e. Salmonella enterica and influenza virus. The knowledge emerging from this work is expected to expand our understanding of innate and adaptive immune responses to infection and pave the road for the development of new therapies and immune interventions against microbial pathogens.
Original text from CORDIS.
Participants
- HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH · BraunschweigCoordinatorGermany
Links
Data: CORDIS, © European Union