Rotavirus acceleration of murine type 1 diabetes is associated with a T helper 1-dependent specific serum antibody response and virus effects in regional lymph nodes

Abstract

Aims/hypothesis Rotavirus infection in at-risk children correlates with production of serum autoantibodies indicative of type 1 diabetes progression. Oral infection with rhesus monkey rotavirus (RRV) accelerates diabetes onset in mice. This relates to their rotavirus-specific serum antibody titre and local pro-inflammatory cytokine induction without pancreatic infection. Our aim was to further investigate the roles of serum antibodies and viral extra-intestinal spread in diabetes acceleration by rotavirus. Methods Rotavirus-specific serum antibody production was detected by ELISA in diabetes-prone mice given either inactivated or low-dose RRV, in relation to their diabetes development. Serum anti-rotavirus antibody titres and infectious virus in lymph nodes were measured in mice given RRV or porcine rotavirus CRW-8. In lymph node cells, rotavirus antigen presence and immune activation were determined by flow cytometry, in conjunction with cytokine mRNA levels. Results Acceleration of diabetes by RRV required virus replication, which correlated with antibody presence. CRW-8 induced similar specific total immunoglobulin and IgA titres to those induced by RRV, but did not accelerate diabetes. RRV alone elicited specific serum IgG antibodies with a T helper (Th)1 bias, spread to regional lymph nodes and activated antigen-presenting cells at these sites. RRV increased Th1-specific cytokine expression in pancreatic lymph nodes. Diabetes onset was more rapid in the RRVinfected mice with the greater Th1 bias. Conclusions/interpretation Acceleration of murine diabetes by rotavirus is virus strain-specific and associated with virus spread to regional lymph nodes, activation of antigenpresenting cells at these sites and induction of a Th1-dominated antibody and cytokine response.

Rotavirus Infection Induces Transient Pancreatic Involution and Hyperglycemia in Weanling Mice

“…In NOD mice, which are genetically prone to immune dysregulation and autoimmune diabetes, RV infection in the neonatal period retarded [29], [30] but at [29] or after [14] weaning accelerated the development of diabetes. However, in these and a further study in NOD mice that described T helper-1 cytokine expression in pancreatic lymph nodes after RRV infection [31], the condition of the pancreas was not reported. Acting as an innate immune trigger, RV double stranded RNA could potentially set the stage for adaptive immunity to beta cells in genetically susceptible hosts.…”

The Virome in Host Health and Disease

“…Infection by rotavirus, a major cause of gastroenteritis in children, is associated with a concurrent increase in autoantibodies in children genetically at-risk for T1D (Honeyman et al, 2000). In non-obese diabetic (NOD) mice with pre-existing autoimmunity, rhesus monkey rotavirus (RRV) accelerates diabetes by infecting lymph nodes and not the pancreas (Graham et al, 2008; Pane et al, 2013). This long-range immunopotentiation is likely mediated by IFN-I, which when produced by lymph node plasmacytoid dendritic cells that take up RRV, induces the activation of uninfected bystander dendritic cells, B cells, and autoreactive T cells (Pane et al, 2014).…”

Potential viral pathogenic mechanism in human type 1 diabetes

“…Recent observations in a virus-based diabetes models of the mouse [17, 71, 72] have taught us that beta-cell-antigen-specific T cells can recruit a high number of non-beta-cell-antigen-specific bystander T cells that add to the destruction of beta cells (more than 98% of infiltrating CD8 cells in the rat insulin promoter–lymphocytic choriomeningitis virus (RIP-LCMV) model are not viral-antigen-specific [17]). From this point of view, any viral infection of pancreatic structures can lead to an accumulation of activated T cells in the immediate vicinity of beta cells, which might significantly affect their health and function.…”