Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA 92093.
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):24998-25007. doi: 10.1073/pnas.2003656117. Epub 2020 Sep 21.
Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio. Remarkably, the most profound microbiome changes occurred transiently after infection with the fast-spreading persistent isolate, were uncoupled from sustained viral loads, and were instead largely caused by CD8 T cell responses and/or CD8 T cell-induced anorexia. Among the taxa enriched by infection with the fast-spreading virus, , broadly regarded as a beneficial commensal, bloomed upon starvation and in a CD8 T cell-dependent manner. Strikingly, oral administration of suppressed selected effector features of CD8 T cells in the context of both infections. Our findings define unique microbiome differences after chronic versus acute viral infections and identify CD8 T cell responses and downstream anorexia as driver mechanisms of microbial dysbiosis after infection with a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest a model in which changes in host behavior and downstream microbiome dysbiosis may constitute a previously unrecognized negative feedback loop that contributes to CD8 T cell adaptations after infections with fast-spreading and/or persistent pathogens.
感染会引发免疫适应，使机体能够抵抗病原体或对其产生耐受性，同时还会引起肠道微生物组的组成变化。然而，人们对于感染具有不同传播和/或持续能力的病原体如何导致微生物组发生变化、其潜在机制以及单个共生物种对免疫细胞适应的相对贡献，仍然缺乏全面的了解。在这里，我们发现，感染快速传播和持续存在（而非缓慢传播和急性）的淋巴细胞性脉络丛脑膜炎病毒会引起大规模的微生物组变化，其特征是厚壁菌门/拟杆菌门比例降低，疣微菌门丰度增加。值得注意的是，与快速传播和持续存在的病毒株感染相关的最显著的微生物组变化是短暂发生的，与持续的病毒载量无关，而是主要由 CD8 T 细胞反应和/或 CD8 T 细胞诱导的厌食引起的。在感染快速传播病毒后丰度增加的分类群中，通常被认为是有益共生体的 ，在饥饿时会大量繁殖，且这种繁殖依赖于 CD8 T 细胞。引人注目的是，在两种感染情况下，口服 均可抑制由快速传播病毒感染引起的 CD8 T 细胞的某些效应特征。我们的研究结果定义了慢性和急性病毒感染后独特的微生物组差异，并确定了 CD8 T 细胞反应和随之而来的厌食是感染快速传播病毒后微生物失调的驱动机制。我们的数据还突出了益生菌的潜在背景依赖性效应，并提出了一个模型，即宿主行为的变化和下游微生物失调可能构成了一个以前未被认识的负反馈回路，有助于快速传播和/或持续存在的病原体感染后的 CD8 T 细胞适应性。
