Recent studies highlight a crucial role for gut mucosal immunity in both gut-proximal autoimmune diseases (Inflammatory Bowel Disease (IBD)) and in those involving extraintestinal compartments (rheumatoid arthritis and multiple sclerosis). The development of autoimmune disease involves the coordination of multiple gut- resident cell types and the gut microbiome. On the host side, immune cells and intestinal epithelium orchestrate gut microbial homeostasis via secretion of effector cytokines, antimicrobial peptides, and other molecules. Microbiota are also important modulators of immune responses, influencing the differentiation and function of immune cell populations. We propose an experimental design that combines IBD-relevant perturbations of host and microbiota. Cell abundance (immune cell and microbiota, Aim 1) and genomic measurements (microbial and host cell transcriptomics, Aim 2) will be combined into an integrated experimental design that will allow us to connect ecological changes in the gut to underlying molecular events in bacteria and host immune cells. We will combine three host perturbations (inhibition of ROR?t, IL-10 and IL- 23) with the introduction of two microbes that induce IBD-relevant phenotypes (Segmented Filamentous Bacteria (SFB) and Helicobacter hepaticus (Hh)) into specific pathogen free mice (mice with """"""""normal"""""""" microbiomes). SFB adheres to the small intestinal epithelium and causes the expansion of Th17 cell populations in the lamina propria, influencing colitis, arthritis- and MS-relevant phenotypes. The commensal Hh promotes an anti-inflammatory immune response to limit its own gut colonization and only induces colitis-like pathologies in mouse strains with disrupted immune function. Hh-dependent murine colitis mirrors human IBD, where otherwise harmless gut microbial perturbations lead to chronic intestinal dysbiosis in genetically immune-deficient hosts. SFB and Hh interact with IL-23 and IL-10 signaling pathways (both strongly implicated in IBD pathogenesis). Blockade of IL-23 signaling contributes to the efficacy of IL-12p40 antibody therapy for IBD and genome-wide association studies confirm a central role for IL-23R in colitis. In humans mutations in IL10R are associated with IBD and IL-10 signaling deficiency in mice leads to spontaneous microbiome- dependent colitis upon Hh colonization. Our matrix of host and immune perturbations will allow us to explore distinct complementary IBD-relevant host responses. We will focus on human-relevant mechanisms by combining our results with existing databases of human genetic variations associated with IBD and autoimmune disease to select host genes that can then be further studied in mouse models along with relevant bacteria and their products (the intersection of our host regulatory network and the set of human orthologs with IBD association, Aim 3). Completion of our study will result in a new quantitative understanding of the large network of interactions between the immune system and the microbiome and will identify molecular mechanisms relevant for designing new interventions for human inflammatory bowel disease.
Approximately 5-8% of Americans suffer from autoimmune diseases, yet even the most prevalent autoimmune diseases have no cure and require costly lifelong immune-suppressive therapies. Growing evidence suggests immunomodulatory roles for microbiota in humans, highlighting the need to understand the large-scale molecular and ecological networks underlying host-microbiome interaction.
|Tchourine, Konstantine; Vogel, Christine; Bonneau, Richard (2018) Condition-Specific Modeling of Biophysical Parameters Advances Inference of Regulatory Networks. Cell Rep 23:376-388|
|Xu, Mo; Pokrovskii, Maria; Ding, Yi et al. (2018) c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554:373-377|
|Bradley, C Pierce; Teng, Fei; Felix, Krysta M et al. (2017) Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs. Cell Host Microbe 22:697-704.e4|
|Karwacz, Katarzyna; Miraldi, Emily R; Pokrovskii, Maria et al. (2017) Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat Immunol 18:412-421|
|Kurtz, Zachary D; Müller, Christian L; Miraldi, Emily R et al. (2015) Sparse and compositionally robust inference of microbial ecological networks. PLoS Comput Biol 11:e1004226|
|Huang, Wendy; Thomas, Benjamin; Flynn, Ryan A et al. (2015) DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528:517-22|
|Sano, Teruyuki; Huang, Wendy; Hall, Jason A et al. (2015) An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses. Cell 163:381-93|
|Longman, Randy S; Littman, Dan R (2015) The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity. Curr Opin Rheumatol 27:381-7|