Innate immune responses to microbial flora

描述(申请人提供)：由高度抗药性微生物引起的感染在住院患者中是一个日益严重的问题。其中许多感染是在抗生素治疗之后发生的，抗生素治疗是一种干预措施，促进了高度抗药性细菌的定居。虽然消除共生菌打开了物理和营养利基，促进抗生素耐药微生物的生长，但我们实验室的结果表明，抗生素也通过干扰共生菌对天然免疫受体的动态平衡刺激，破坏粘膜表面的天然免疫防御。这项应用的重点是表征肠道微生物和粘膜天然免疫系统之间的关系。我们的实验方法将是操纵共生菌群或先天性免疫系统，并衡量宿主抵抗万古霉素耐药肠球菌(VRE)和碳青霉烯耐药肺炎克雷伯菌(KPC)的定植和感染的能力。这两种细菌对抗生素具有高度耐药性，是严重、经常致命感染的新兴原因。我们的第一个目标是确定不同的抗生素对小鼠肠道共生菌的影响，以及抗生素对肠道上皮细胞天然免疫效应分子表达的下游影响。我们研究的第二个目的是确定先天免疫受体缺陷对小鼠肠道菌群的影响。这些研究将利用我们动物群体中大量的TLR和信号转接器突变小鼠品系。我们的第三个目标是测试不同的微生物分子或类似物在抗生素治疗耗尽共生菌群的小鼠中刺激对VRE和KPC的天然免疫防御的能力。我们相信，这些研究将为微生物菌群和肠道上皮之间的双向关系提供重要的见解。我们的研究可能会提供新的方法来预防或限制由高度抗药性细菌引起的感染。与公共卫生相关：在接受抗生素治疗的患者中，感染高度耐药细菌是一个越来越常见的问题。我们已经发现，抗生素通过消除寄生在肠道中的正常细菌，损害了肠道衬里抵抗耐药细菌攻击的能力。我们的实验将确定哪些正常的肠道细菌对维持肠道中的抗菌素耐药性是重要的，以及哪些哺乳动物分子负责检测肠道中的正常细菌。我们的第三个目标是发现给予来自细菌的分子是否可以逆转由于给予抗生素而增加的感染敏感性。

DESCRIPTION (provided by applicant): Infections caused by highly antibiotic-resistant microbes are an increasing problem in hospitalized patients. Many of these infections occur following antibiotic therapy, an intervention that promotes colonization with highly antibiotic-resistant bacteria. Although elimination of commensal bacteria opens up physical and nutrient niches that enhance growth of antibiotic resistant microbes, results from our laboratory suggest that antibiotics also compromise innate immune defenses on mucosal surfaces by interfering with homeostatic stimulation of innate immune receptors by commensal flora. The focus of this application is to characterize the relationship between intestinal microbes and the mucosal innate immune system. Our experimental approach will be to manipulate the commensal flora or the innate immune system and measure the host's ability to resist colonization and infection by Vancomycin-resistant enterococcus (VRE) and carbapenem-resistant Klebsiella pneumoniae (KPC), two highly antibiotic resistant bacteria that are emerging causes of severe, frequently lethal infections. Our first aim is to characterize the effect of distinct antibiotics on the commensal flora of the murine gut and the downstream effect of antibiotics on the expression of innate immune effector molecules by the intestinal epithelium. The second aim of our studies is to determine the effect of innate immune receptor deficiencies on the flora of the murine intestinal tract. These studies will take advantage of a large panel of TLR and signaling adaptor mutant mouse strains in our animal colony. Our third aim is to test the ability of different microbial molecules or analogs to stimulate innate immune defense against VRE and KPC in mice depleted of commensal flora by antibiotic treatment. We believe these studies will provide important insights into the two-way relationship between the microbial flora and the intestinal epithelium. Our studies are likely to provide new approaches to prevent or limit infections caused by highly antibiotic-resistant bacteria. PUBLIC HEALTH RELEVANCE: Infections with highly antibiotic-resistant bacteria are an increasingly common problem in patients being treated with antibiotics. We have discovered that antibiotics, by eliminating normal bacteria inhabiting the intestine, compromise the ability of the intestinal lining to resist attack by antibiotic-resistant bacteria. Our experiments will determine which normal intestinal bacteria are important for the maintenance of antimicrobial resistance in the intestine, and which mammalian molecules are responsible for detecting normal bacteria in the intestine. Our third aim is to discover whether administration of molecules derived from bacteria can reverse the increased susceptibility to infection induced by antibiotic administration.