Genetic background modifies host and viral parameters of neonatal gammaherpesvirus infection

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with cancer and multiple sclerosis. Primary infection during adolescence significantly increases the risk of gammaherpesvirus-driven disease in humans. Correspondingly, infection of adolescent mice with murine gammaherpesvirus 68 (MHV68) has served as a tractable animal model to define host factors that control chronic gammaherpesvirus infection and pathogenesis. However, a majority of humans are infected with gammaherpesviruses during early life when the nature of adaptive immune responses is altered as compared to that of older children and adults. Given that human and murine gammaherpesviruses manipulate B cell differentiation to establish the latent reservoir in adolescents, this study aims to define the host and viral parameters of chronic gammaherpesvirus infection following neonatal inoculation. Similar to adolescents, MHV68-driven germinal center responses and the establishment of a latent viral reservoir in splenic germinal center B cells of BALB/c mice were reliably observed following neonatal intranasal infection with 400 PFU of MHV68. Unexpectedly, MHV68-driven splenomegaly, a ubiquitous clinical manifestation of gammaherpesvirus infection in recently infected adolescent mice and humans, was only observed in neonatally infected BALB/c males and not females. Interestingly, C57BL/6J neonates were largely resistant to the establishment of latent splenic infection following 400 PFU intranasal inoculation. Increasing the MHV68 inoculum rescued the establishment of chronic splenic infection and MHV68-driven germinal center responses in neonatally infected C57BL/6J mice. Thus, the current study unveils the role of genetic background and early life exposure in the susceptibility to systemic gammaherpesvirus infection.IMPORTANCEPrimary gammaherpesvirus infection of adolescents is associated with increased risk of gammaherpesvirus-driven disease, such as cancer and multiple sclerosis. Therefore, the murine gammaherpesvirus 68 (MHV68) animal model has served as a tractable experimental system to define host factors involved in control of gammaherpesvirus infection and pathogenesis following adolescent infection. However, a majority of human gammaherpesvirus infections occur during early childhood, a stage of human development that is marked by unique differences in the adaptive immune responses as compared to that of adults. This study demonstrates that the genetic background plays an important role in limiting systemic gammaherpesvirus infection following neonatal viral exposure, in contrast to that historically observed in primary adolescent infection. However, when susceptible to systemic infection, the extent of MHV68-driven germinal center responses and establishment of a latent viral reservoir in germinal center B cells are largely comparable between neonatally infected mice and published observations in adolescent MHV68 infection.