Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

Abstract

Aims/hypothesis Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring.Methods The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. Results Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. Conclusions/interpretation Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes.

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

“…Third, the discovery of protective viruses fits with immunological crossprotection attenuating infections caused by closely related viruses. Fourth, the observation that maternal CVB1 antibodies modulated the risk effect of CVB1 supports biological plausibility because maternal antibodies protect the child against enterovirus infections (43,44). Finally, we observed a similar risk effect of CVB1 in another study where neutralizing antibodies were analyzed in patients with newly diagnosed type 1 diabetes and control subjects in five European countries (41).…”

Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes

“…This hypothesis is based on an analogous experience from another EV disease, paralytic poliomyelitis, which is the well-known complication of poliovirus infection and similarly associated with a low frequency of poliovirus infections in the population (28). The polio hypothesis has recently been supported by mouse studies, showing that the absence of maternal EV antibodies increases the risk for severe outcomes of an EV infection in offspring (29). However, in the present study this relationship was not absolute because, for example, Sweden had a relatively high frequency of infections but has a high incidence of type 1 diabetes.…”

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

“…Blood glucose level measurements and diabetes monitoring Diabetes development in NOD mice was monitored by weekly blood glucose measurements as previously described [31].…”

“…Antibody titrations Antibody titrations were carried out as previously described [31], with the following modifications: 50 plaque-forming units (PFU) of CVB1 were used and cells were cultured in 12-well plates using a plaque assay medium containing 2/3 volumes Minimal Essential Medium and 1/3 volume Hanks' balanced salt solution, supplemented with 1.33% (vol./vol.) FBS, 33 U/ml penicillin, 330 μg/ml streptomycin, 1.33 mmol/l L-glutamine and 0.66% (wt/vol.)…”