Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection

Abstract

Group B coxsackieviruses (CVB) are believed to trigger some cases of human type 1 diabetes (T1D), although the mechanism by which this may occur has not been shown. We demonstrated previously that inoculation of young nonobese diabetic (NOD) mice with any of several different CVB strains reduced T1D incidence. We also observed no evidence of CVB replication within islets of young NOD mice, suggesting no role for CVB in T1D induction in the NOD mouse model. The failure to observe CVB replication within islets of young NOD mice has been proposed to be due to interferon expression by insulin-producing beta cells or lack of expression of the CVB receptor CAR. We found that CAR protein is detectable within islets of young and older NOD mice and that a CVB3 strain, which expresses murine IL-4, can replicate in islets. Mice inoculated with the IL-4 expressing CVB3 chimeric strain were better protected from T1D onset than were mock-infected control mice despite intraislet viral replication. Having demonstrated that CVB can replicate in healthy islets of young NOD mice when the intraislet environment is suitably altered, we asked whether islets in old prediabetic mice were resistant to CVB infection. Unlike young mice in which insulitis is not yet apparent, older NOD mice demonstrate severe insulitis in all islets. Inoculating older prediabetic mice with different pathogenic CVB strains caused accelerated T1D onset relative to control mice, a phenomenon that was preceded by detection of virus within islets. Together, the results suggest a model for resolving conflicting data regarding the role of CVB in human T1D etiology.

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

“…Prevention of lethal CVB1 infection by a prior CVB3 infection has also been observed in a mouse model, fitting nicely with the findings in the current study (38). In addition to crossprotection, other mechanisms related to the induction of b-cell tolerance may mediate the protective effect of viruses against type 1 diabetes as described in NOD mice (39,40). In both cases, the close relationship between the protective and the diabetogenic serotypes suggests a particular impact of the CVB group enteroviruses on the risk of diabetes.…”

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

“…This observation, which obscures a simple definition of a diabetogenic CVB phenotype, is consistent with CVB diabetogenicity being modulated by the host environment. The impact of the host environment on viral replication is well-established: expression of CVB phenotypes are modulated by a variety of influences, including immune status, age, strain, and gender of the mouse host (14,23,25,49,50).To test the hypothesis whether diabetogenicity is a common phenotype, we used a well-characterized, poorly pathogenic CVB3 strain, CVB3/GA (33,55,56), reasoning that rapid T1D onset should not be observed if the virus lacks a putative …”

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

“…The 11 viral proteins (83) are encoded by a single open reading frame which is flanked on the 5Ј and 3Ј termini by nontranslated regions (NTRs) (20). The CVB induce numerous human illnesses, including inflammatory heart disease, pancreatitis, and aseptic meningitis and may also trigger the onset of type 1 diabetes (5,31,72,81,82). The CVB were recognized as causes of human heart disease shortly after their description early in the 1950s (26,27) and remain the enteroviruses most commonly associated with human cardiomyopathies on the grounds of isolation and serology (5,6,34,62,88).…”

“…Meta-analysis shows an association between enteroviruses and myocarditis in 23% of cases (7), although this association is more variable in cases of dilated cardiomyopathy, a serious disease that often leads to a failing heart (61). Mouse models of CVB-induced pancreatitis (94,110), myocarditis (45,52,110), myositis (104,105), and rapid-onset type 1 diabetes (31) which facilitate the study of these diseases have been developed.…”