title: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Margo C
authors.initials: MC
authors.lastname: Honeyman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Laine
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Londrigan
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Carl
authors.initials: C
authors.lastname: Kirkwood
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000821:virology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D012038:Regeneration; D012401:Rotavirus / Q000502:physiology*; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014886:Weaning
chemical_list: D007328:Insulin; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3