Coxsackievirus infections have been proposed as an environmental trigger for the development of T-cell-mediated autoimmune (type 1) diabetes by either providing a molecular mimic of the candidate pancreatic -cell autoantigen GAD or inducing bystander inflammation in the pancreas. In this study in the NOD mouse model, we found that infection with a pancreatrophic coxsackievirus isolate can accelerate type 1 diabetes development through the induction of a bystander activation effect, but only after a critical threshold level of insulitic -cell-autoreactive T-cells has accumulated. Thus, coxsackievirus infections do not appear to initiate -cell autoreactive immunity but can accelerate the process once it is underway. These findings indicate that the timing of a coxsackievirus infection, rather than its simple presence or absence, may have important etiological implications for the development of T-cell-mediated autoimmune type 1 diabetes in humans. Diabetes 49:708-711, 2000 T -cell-mediated autoimmune (type 1) diabetes in both humans and NOD mice is controlled by multiple susceptibility genes whose pathogenic functions can be modulated by various environmental factors (1-3). Coxsackieviral infections may represent one environmental factor that could contribute to type 1 diabetes development in genetically susceptible individuals (4). An antigenic epitope derived from the 65-and 67-kDa isoforms of GAD and proposed to be one of the earliest targets of diabetogenic CD4 + T-cell responses in NOD mice is characterized by a PEVKEK sequence also found within a peptide consisting of amino acids 28-50 from the coxsackievirus P2C protein (Cox sequence similarity peptide [ssp]) (5). Thus, one mechanism by which a coxsackievirus infection could contribute to type 1 diabetes is by providing a molecular mimic during replication that triggers a cross-reactive CD4 + T-cell response against the candidate -cell autoantigen GAD. Arguing against this molecular mimicry hypothesis was a report that GAD reactive T-cell responses were not enhanced in NOD mice after a coxsackievirus infection (6). Instead, this earlier study found that the coxsackievirus B4 Edwards strain (CVB4) can accelerate type 1 diabetes development in a T-cell receptor (TCR) transgenic stock of NOD mice in which virtually all T-cells are of the CD4 + BDC2.5 clonotype that recognizes a -cell autoantigen other than GAD. This finding was interpreted to mean that rather than providing a molecular mimic of GAD, infection with the pancreatrophic CVB4 isolate contributes to type 1 diabetes development by stimulating a local inflammatory response that leads to subclinical levels of -cell destruction and the subsequent release of normally sequestered antigens, which then trigger pathogenic autoreactive T-cell responses. However, this interpretation does not explain why, in that previous study, CVB4 infection failed to elicit type 1 diabetes development in standard nontransgenic NOD mice that are characterized by not only the presence of BDC2.5 clonotypic T-cells, but al...
The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.
Group B coxsackieviruses are etiologically linked to many human diseases, and cell surface receptors are postulated to play an important role in mediating their pathogenesis. The coxsackievirus adenovirus receptor (CAR) has been shown to function as a receptor for selected strains of coxsackievirus group B (CVB) serotypes 3, 4, and 5 and is postulated to serve as a receptor for all six serotypes. In this study, we demonstrate that CAR can serve as a receptor for laboratory reference strains and clinical isolates of all six CVB serotypes. Infection of CHO cells expressing human CAR results in a 1000-fold increase in CVB progeny virus titer compared to mock transfected cells. CAR was shown to be a functional receptor for swine vesicular disease virus (SVDV), as CHO-CAR cells but not CHO mock transfected controls were susceptible to SVDV infection, produced progeny SVDV, and developed cytopathic effects. Moreover, SVDV infection could be specifically blocked by monoclonal antibody to CAR (RmcB). SVDV infection of HeLa cells was also inhibited by an anti-CD55 MAb, suggesting that this virus, like some CVB, may interact with CD55 (decay accelerating factor) in addition to CAR. Finally, pretreatment of CVB or SVDV with soluble CAR effectively blocks virus infection of HeLa cell monolayers.
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