Prior immune exposure can protect or can enhance pathology in the enteroviruses: what predicts the outcome?

In this issue of Virulence, Elmastour et al. link the increased pathology of secondary coxsackievirus infections to enhancement of infection by antibody to the coxsackievirus. This editorial demonstrates that this is a phenomenon has been found in other murine models of human disease in which enterovirus persists beyond the acute stage. How is it possible for a second enterovirus infection to lead to more severe disease even when the infection is of the same serotype? The poliovirus vaccines have demonstrated the ability of enteroviruses to generate an immune response capable of preventing a pathogenic level of secondary infection. However, Elmastour et al as well as several previous studies using the mouse model of infection with coxsackievirus B (CVB) serotypes have demonstrated that enteroviruses can result in an enhanced level of disease in both the heart and the pancreas after a second infection. This has been attributed to effects of antigenic mimicry in which the immune response, including the antibody response, reacts to non-viral antigens in the tissue, to a primed T cell response via common epitopes resulting in increased inflammation, to bystander activation of autoimmunity which is enhanced by repetitive infections or to antibody dependent enhancement (ADE) of disease via increased uptake of viruses and infection of monocytes or macrophage resulting in spread of the virus to tissues and protection from the adaptive immune response. The latter phenomenon has been explored in studies of dengue virus disease (reviewed). As observed in the murine model, the second infection with an enterovirus can only enhance disease because the primary infection does not provide sufficient immune response to permit sufficient virus clearance. Clearly when homotypic secondary infections occur, there is a low level of effective antibody response in animals in which if the second infection occurs to any extent. In the current study by Dr. Hober and colleagues, the secondary infection is successful and enhances the degree of disease over that seen with just a primary infection at the time of the secondary infection. In homotypic secondary enterovirus infections in which higher levels of neutralizing antibody are induced by the primary infection, there is protection against the secondary infection and only in cases in which there is a reduced immune response to the primary infection, does a secondary infection increase the level of disease observed over that from a primary infection alone. When heterotypic infections are used, the immune response from the first infection is likely to be less able to provide protective immunity against the second infection due to dissimilarity in the viral antigens. In several studies using heterotypic enterovirus infections in the murine model, the prior infection increases the extent of disease induced by the infection of the second enterovirus serotype. An exception to this was an observation of weanling CD-1 mice inoculated with CVB3 in which some degree of reduction of myocarditis was observed when the mice had survived an earlier infection with CVB4. When the secondary enterovirus infection enhances pathology, there is an association with increased viral load of the secondary infection. In Elmastour et al, A/J mice with a prior infection at 21 d of age with CVB4 and another at day 55 have levels of viral RNA and cytopathic virus at days 72 and 89 which are increased beyond an additive amount from mice inoculated only once. There was significant increase in viral RNA in the heart and pancreas in A/J mice with a prior CVB2 infection upon challenge with CVB3 in another study of