CAREER: Investigating the role of MHC during assembly of commensal microbial communities

哺乳动物是一个巨大的共生细菌联盟的家园，这些细菌有助于塑造和维持宿主的健康。虽然一些寄生微生物对宿主有益，但另一些却是有害的。致病细菌和共生细菌有许多相同的分子基序，这使得宿主免疫系统如何区分有益和有害的细菌物种变得不清楚。脊椎动物拥有一个独特的基因家族，即主要组织相容性复合体(MHC)，它允许激活针对特定微生物的定制免疫反应。MHC基因座的基本功能是让免疫系统区分“自我”和“非自我”组织，从而让免疫系统摧毁微生物入侵者，同时防止免疫系统攻击动物自身的细胞。然而，研究人员提出了MHC的另一个迄今未被认识到的作用：MHC进化的一个主要推动力，除了它在动物“自我”识别和根除病原体方面的长期已知作用外，还需要动物与它们的共生微生物群落保持一种动态平衡关系。该项目将使用遗传和分子方法以及微生物区系转移到无菌小鼠中来验证这一新的假设。这些研究有可能揭示微生物群落是如何在宿主内构建的，并确定宿主和微生物交流的新原则。如果MHC被证明管理着共生群落的集合，那么动物的“自我”将需要重新定义，不仅包括宿主动物本身，还包括动物的共生微生物区系。该项目的教育目标包括本科生、研究生和博士后的研究培训。此外，这位调查人员和她的学生将与当地一家自然历史博物馆的工作人员合作，创建一个夏令营，向中学生传授他们自己的共生微生物区系。

Mammals are home to a vast consortium of commensal bacteria that help shape and maintain host health. While some resident microbes have beneficial consequences to the host, others are detrimental. Pathogenic and commensal bacteria share many of the same molecular motifs, making it unclear how the host immune system discriminates between beneficial and harmful bacterial species. Vertebrates possess a unique gene family, the major histocompatibility complex (MHC),that allows for activation of a tailored immune response toward a specific microbe. The fundamental function of the MHC gene locus is to allow the immune system to discriminate between "self" and "non-self" tissue, thus allowing the immune system to destroy microbial invaders, while preventing the immune system from attacking cells of the animal's own body. However, the investigators propose an additional, thus far un-appreciated role for the MHC: that a major driving force in the evolution of the MHC, beyond its long-known roles in animal "self" recognition and eradication of pathogens, is the need for animals to maintain a homeostatic relationship with their commensal microbial communities. This project will test this novel hypothesis using genetic and molecular approaches coupled with microbiota transfers into germfree mice. These studies have the potential to reveal how microbial communities are constructed within the host and to identify novel principles by which the host and microbes communicate. If the MHC is proven to govern the assembly of commensal communities, then animal "self" will need to be redefined to include not just the host animal itself, but also the animal's commensal microbiota. Educational goals of this project include research training for undergraduate, graduate and postdoctoral students. In addition, the investigator and her students will work with staff of a local natural history museum to create a summer science camp that teaches middle school children about their own commensal microbiota.