Rotavirus Infection Induces Transient Pancreatic Involution and Hyperglycemia in Weanling Mice

Abstract

Rotavirus is a ubiquitous double-stranded RNA virus responsible for most cases of infantile gastroenteritis. It infects pancreatic islets in vitro and is implicated as a trigger of autoimmune destruction of islet beta cells leading to type 1 diabetes, but pancreatic pathology secondary to rotavirus infection in vivo has not been documented. To address this issue, we inoculated 3 week-old C57Bl/6 mice at weaning with rhesus rotavirus, which is closely related to human rotaviruses and known to infect mouse islets in vitro. Virus was quantified in tissues by culture-isolation and enzyme-linked immunosorbent assay. A requirement for viral double stranded RNA was investigated in toll-like receptor 3 (TLR3)-deficient mice. Cell proliferation and apoptosis, and insulin expression, were analyzed by immunohistochemistry. Following rotavirus inoculation by gavage, two phases of mild, transient hyperglycemia were observed beginning after 2 and 8 days. In the first phase, widespread apoptosis of pancreatic cells was associated with a decrease in pancreas mass and insulin production, without detectable virus in the pancreas. These effects were mimicked by injection of the double-stranded RNA mimic, polyinosinic-polycytidylic acid, and were TLR3-dependent. By the second phase, the pancreas had regenerated but islets were smaller than normal and viral antigen was then detected in the pancreas for several days. These findings directly demonstrate pathogenic effects of rotavirus infection on the pancreas in vivo, mediated initially by the interaction of rotavirus double-stranded RNA with TLR3.

Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling

“…As the NOD mouse genetic background and pre-existing islet autoimmunity are important preconditions for diabetes acceleration following rotavirus infection, it is unlikely that the type I interferon signalling induced by RRV in C57BL/6 mice would facilitate autoimmunity 9 10 . Consistent with this, only a very mild, transient hyperglycaemia may be present in association with RRV inoculation of C57BL/6 mice 28 . Rather, the ability of RRV infection to induce type I interferon secretion by pDCs in the lymph nodes appears to be the defining factor associated with diabetes acceleration.…”

Effects of Escherichia coli Nissle 1917 and Ciprofloxacin on small intestinal epithelial cell mRNA expression in the neonatal piglet model of human rotavirus infection

“…We conclude that HRV infection might induce apoptosis of mature enterocytes as observed by others for murine RV [30] and, consequently, stimulate IEC proliferation. However, these cells are replaced by less differentiated enterocytes, leading to defective absorptive function and increased secretory HRV diarrhea [30, 32]. …”

Metabolic changes in type 2 diabetes are reflected in peripheral blood cells, revealing aberrant cytotoxicity, a viral signature, and hypoxia inducible factor activity

“…Interestingly, reoviruses are known to experimentally induce type 1 diabetes, by inducing insulitis, reduction in insulin content of the pancreas and abnormal glucose tolerance [ 46 , 47 ]. Likewise, Rotavirus infection is associated with a faster progression of diabetes in diabetes-prone mice [ 48 ] and with pancreatic apoptosis and hyperglycemia in nondiabetes-prone mice [ 49 ]. Previous studies already pointed towards a role for viruses in development human T1DM.…”