Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
California National Primate Research Center, Davis, California, USA.
J Virol. 2018 Jun 13;92(13). doi: 10.1128/JVI.00167-18. Print 2018 Jul 1.
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 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. 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.
亚临床病毒感染（SVI），包括巨细胞病毒（CMV），在人类中非常普遍，导致终身持续存在。然而，SVI 对宿主免疫与肠道微生物群在环境暴露背景下相互作用的影响尚未得到明确界定。我们利用由无 SVI（无特定病原体[SPF]）恒河猴组成的临床前非人类灵长类动物（NHP）模型，并将其与通过自然暴露获得 SVI（非 SPF）的动物进行比较，研究 SVI 对免疫细胞分布和功能以及肠道微生物群的影响。这些变化在户外环境中饲养的动物与在受控室内环境中饲养的动物中进行了检查。我们报告称，SVI 与户外环境中饲养的动物的免疫细胞亚群和肠道微生物群组成的改变有关。非 SPF 动物具有更高比例的潜在丁酸产生菌和更高数量的淋巴细胞、效应 T 细胞和细胞因子产生 T 细胞。令人惊讶的是，这些差异在它们转移到受控室内环境后消失了，这表明非 SPF 动物对环境暴露的反应性增强。用 CMV 对室内 SPF 动物进行实验性感染导致丁酸产生菌的丰度增加，验证了 CMV 增强了丁酸产生共生菌的定植。最后，与 SPF 动物相比，非 SPF 动物对流感疫苗的抗体反应较低。我们的数据表明，亚临床 CMV 感染会增强宿主免疫和肠道微生物群对环境暴露的变化作出反应。这可能导致人群水平对疫苗和环境刺激的宿主免疫反应出现异质性。人类携带几种调节宿主免疫和共生微生物群的潜伏病毒，从而导致其对病原体、疫苗和环境暴露的反应出现异质性。我们对 CMV 对免疫系统影响的大部分了解是基于儿童感染 CMV 或免疫功能低下的人患有急性或再激活的 CMV 感染或老年人的研究，或在遗传上同质的实验小鼠模型中进行的。实验小鼠模型是遗传同系的，完全适应室内实验室环境。相比之下，非人类灵长类动物是遗传异质的，在户外环境中饲养。我们的研究首次报告了长期亚临床 CMV 感染对宿主免疫和肠道微生物群的影响，这种影响仅在户外环境中可见，而在室内环境中不可见。这项研究的意义在于强调 SVI 对增强宿主对环境暴露的免疫易感性和免疫异质性的影响。
