Virus-mediated dysbiosis alters immune populations to promote type 1 diabetes onset

Abstract

Abstract In combination with genetic determinants, susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D) is established by various environmental factors including infection, microbial dysbiosis, antibiotic use, and vitamin D deficiency. Studies have implicated infection with certain viruses such as coxsackievirus B (CVB) to be an important cofactor associated with diabetes development and pathogenesis. Infections may be an instigating factor to alter the microbiome and this microbial change may be sufficient to skew immune populations and promote autoimmunity. Mucosa-associated invariant T (MAIT) cell populations have been shown to be altered leading up to diabetes onset in patients and mice. These cells are activated by microbial products in the gut to promote intestinal integrity, but they can also take on a more inflammatory phenotype and participate in autoimmune responses in the pancreas. Ultimately, there exists a significant potential for cross-talk between CVB infection, the microbiome, and gut-resident immune cells impacting T1D susceptibility. We have found CVB infection not only promotes onset of T1D in non-obese diabetic (NOD) mice but also causes dysbiosis which resembles that of a spontaneously diabetic NOD mouse. Introducing this new infection-induced microbial composition into naïve mice through the use of fecal microbiome transfers (FMTs) can accelerate T1D onset and alter immune profiles in the gut as well as the pancreas. Furthermore, MAIT populations are altered by this “diabetogenic” microbiome and also respond directly to CVB infection. Together our data highlights the role of virus infection and its ability to affect the gut microbiome and immune homeostasis to contribute to T1D development.