Abstract
Environmental factors contribute to Type 1 diabetes (T1D) susceptibility. The gut microbiome, which includes bacteria, viruses, and fungi, contributes to this environmental influence, and can induce immunological changes. The gut viral component of the microbiome, related to T1D has mostly focused on coxsackieviruses and rotavirus. The role of norovirus, another common enteric virus, in susceptibility to T1D was hitherto unknown. Norovirus is highly infectious and encountered by many children. We studied the mouse norovirus 4 (MNV4), related to human noroviruses, in the Non-obese diabetic (NOD) mouse model, to determine its role in influencing susceptibility to T1D. We infected MNV-free NOD mice with MNV4 by exposing the mice to MNV4-positive bedding from an endemically-infected mouse colony to mimic a natural infection. Control MNV-free NOD mice were exposed to MNV-free bedding from the same colony. Interestingly, MNV4 infection protected NOD mice from the development of T1D and was associated with an expansion of Tregs and reduced proinflammatory T cells. We also found MNV4 significantly modified the gut commensal bacteria composition, promoting increased α-diversity and Firmicutes/Bacteroidetes ratio. To elucidate whether T1D protection was directly related to MNV4, or indirectly through modulating gut microbiota, we colonized germ-free (GF) NOD mice with the MNV4-containing or non-MNV4-containing viral filtrate, isolated from filtered fecal material. We found that MNV4 induced significant changes in mucosal immunity, including altered Tuft cell markers, cytokine secretion, antiviral immune signaling markers, and the concentration of mucosal antibodies. Systemically, MNV4-infection altered the immune cells including B cell subsets, macrophages and T cells, and especially induced an increase in Treg number and function. Furthermore, in vitro primary exposure of the norovirus filtrate to naïve splenocytes identified significant increases in the proportion of activated and CTLA4-expressing Tregs. Our data provide novel knowledge that norovirus can protect NOD mice from T1D development by inducing the expansion of Tregs and reducing inflammatory T cells. Our study also highlights the importance of distinguishing the mucosal immunity mediated by bacteria from that by enteric viruses.
Highlights
Type 1 diabetes (T1D) is a T cell mediated autoimmune disease resulting from the destruction of insulin-producing pancreatic β-cells
To determine whether norovirus can alter the susceptibility of Non-obese Diabetic (NOD) mice to development of type 1 diabetes, Murine norovirus (MNV)-free NOD mice were exposed at 4–5-weeks of age to bedding from either MNV- or MNV+ cages, of mice housed in the same facility
Enteric viruses, have been linked to the development of T1D [12,13,14,15, 18, 20, 43, 52, 53]; most of these studies have focused on the coxsackievirus or rotavirus, little is known the role of norovirus in T1D development
Summary
Type 1 diabetes (T1D) is a T cell mediated autoimmune disease resulting from the destruction of insulin-producing pancreatic β-cells. Increasing evidence suggests that environmental factors can contribute to the risk of T1D development. Studies in both animal models and humans have identified changes in the bacterial component of the gut microbiota composition in individuals with T1D or “at-risk” compared to controls [1,2,3,4,5,6,7,8,9,10,11]. Enteric viruses, such as the Coxsackieviruses and Rotavirus have been associated with the development of T1D in both humans and mouse models [12,13,14,15,16,17,18,19,20,21]. Little is known about other viruses including norovirus in relation to T1D development
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
