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Morse, Zachary James

University of British Columbia

Autoimmune disorders like type 1 diabetes (T1D) are complex diseases caused by numerous factors including both genetic variance and environmental factors. Two such factors, enterovirus infection and disruption of the intestinal microbiota, have been independently associated with T1D onset in both humans and animal models. Existing research has established a gut-pancreas interaction that links dysbiosis and inflammatory events within the gastro-intestinal (GI) environment to pancreatic immune homeostasis. Thus, I hypothesized that modulation of gut homeostasis due to infection with a T1D-associated virus, coxsackievirus B4 (CVB4) can shape autoreactive potential and pathology within the islet microenvironment. To determine the link between virus infection and the microbiome, non-obese diabetic (NOD) mice were infected with CVB4 and changes in the microbiome and GI homeostasis were observed. Infection accelerated diabetes autoimmunity and caused restructuring of intestinal microbial community composition as well as alteration of intestinal physiology exhibited by eroded mucosal barriers, increased intestinal permeability, bacterial translocation, and modulation of anti-commensal bacteria antibody production. These findings support an overlap in known environmental risk factors of T1D and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D. Commensal microbes influence host immunity through production of small molecule metabolites including short-chain fatty acids (SCFAs) to skew host immunity. Targeted metabolomics and supplementation of mice with exogenous SCFAs prior to CVB4 infection determined both how virus infection modifies the functional activity of the microbiome as well as the ability of bacterial metabolites to affect virus-accelerated diabetes. Collectively, these results suggest bacteria-produced metabolites may protect from virus-induced diabetes autoimmunity. The events within pancreatic tissues leading to T1D are not entirely understood and disruption of immune homeostasis within the pancreas is detrimental for T1D development. Flow cytometry was used to characterize how infection with CVB4 can alter immune profiles in the islets to promote inflammation and destruction of the insulin-secreting beta cells leading to T1D onset. Ultimately, CVB4 infection promoted autoreactive tissue-resident memory T (TRM) cells to invade the islet microenvironment, suggesting this cell population represents a particularly pathogenic T cell subset that contributes to diabetes autoimmunity in NOD mice.

Text

2023-08-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85638

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/