Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Abstract

Subclinical viral infections (SVI), including cytomegalovirus (CMV), are highly prevalent in humans, resulting in lifelong persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (specific-pathogen-free [SPF]) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function, as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producing Firmicutes and higher numbers of lymphocytes, effector T cells, and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level. IMPORTANCE Humans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines, and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immunocompromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.

Limited Impact of Human Cytomegalovirus Infection in African Infants on Vaccine-Specific Responses Following Diphtheria-Tetanus-Pertussis and Measles Vaccination

“…Sex differences in the gut microbiota may also play a role (41) given the studies suggesting that the microbiota influences vaccine-specific immunity (42). Furthermore, non-human primate studies suggest that latent HCMV infection alters the gut microbiota composition, which the authors propose could lead to heterogeneity in responses to vaccines (43), although this has not been studied in humans.…”

The Impact of the Microbiome on Immunity to Vaccination in Humans

“… ( Lynn et al., 2018 ) TIV Rhesus macaques Subclinical CMV infection resulted in increase in butyrate-producing bacteria and lower antibody responses to influenza vaccination. ( Santos Rocha et al., 2018 ) Correlative human studies RV Ghanaian and Dutch infants Microbiome composition was different between RV responders and non-responders. Ghanaian responders were more similar to Dutch infants than to non-responders.…”

Role of Human Pegivirus Infections in Whole P. falciparum Sporozoite Vaccination and Controlled Human Malaria Infection in African Volunteers

“…Clinically silent, chronic viral infections are known to modulate host immunity [17] and in turn, acute co-infections are known to drive the re-activation of asymptomatic viral infections [87].…”