Preexisting helminth challenge exacerbates infection and reactivation of gammaherpesvirus in tissue resident macrophages

Even though gammaherpesvirus and parasitic infections are endemic in parts of the world, there is a lack of understanding about the outcome of coinfection. In humans, coinfections usually occur sequentially, with fluctuating order and timing in different hosts. However, experimental studies in mice generally do not address the variables of order and timing of coinfections. We sought to examine the variable of coinfection order in a system of gammaherpesvirus-helminth coinfection. Our previous work demonstrated that infection with the intestinal parasite, Heligmosomoides polygyrus, induced transient reactivation from latency of murine gammaherpesvirus-68 (MHV68). In this report, we reverse the order of coinfection, infecting with H. polygyrus first, followed by MHV68, and examined the effects of preexisting parasite infection on MHV68 acute and latent infection. We found that preexisting parasite infection increased the propensity of MHV68 to reactivate from latency. However, when we examined the mechanism for reactivation, we found that preexisting parasite infection increased the ability of MHV68 to reactivate in a vitamin A dependent manner, a distinct mechanism to what we found previously with parasite-induced reactivation after latency establishment. We determined that H. polygyrus infection increased both acute and latent MHV68 infection in a population of tissue resident macrophages, called large peritoneal macrophages. We demonstrate that this population of macrophages and vitamin A are required for increased acute and latent infection during parasite coinfection. Coinfections, or concomitant infections with different pathogens, happen regularly in the natural world. We investigated coinfection with an intestinal parasite and a gammaherpesvirus in mice to determine how prior helminth challenge affects chronic herpesvirus infection and reactivation. In our previous reports where we infected with gammaherpesvirus first followed by intestinal parasite, we found that parasite challenge increased reactivation of the virus. In this study, we find that prior infection with helminth leads to increased viral infection of tissue resident macrophages during acute and chronic herpesvirus infection. During the chronic phase of infection, the coinfected mice had more latent infection in tissue resident macrophages and reactivated more herpesvirus. This work suggests that helminth infections exacerbate chronic herpesvirus infection. Importantly, the mechanism by which this occurs is dependent on the order of coinfection.