Innate immune responses to microbial flora

描述（由申请人提供）：由高度耐药微生物引起的感染是住院患者中日益严重的问题。许多这些感染发生在抗生素治疗之后，这种干预促进了高度耐抗生素细菌的定植。虽然共生菌的消除打开了物理和营养生态位，促进了抗生素耐药微生物的生长，但我们实验室的结果表明，抗生素也会通过干扰共生菌群对先天免疫受体的稳态刺激而损害粘膜表面的先天免疫防御。本应用的重点是表征肠道微生物和粘膜先天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免疫系统，并测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）定植和感染的能力，这两种高度耐抗生素的细菌是严重的，经常致命的感染的新原因。我们的第一个目的是表征不同抗生素对小鼠肠道共生菌群的影响，以及抗生素对肠道上皮先天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。这些研究将在我们的动物群体中利用大量的TLR和信号适配器突变小鼠菌株。我们的第三个目标是测试不同微生物分子或类似物在抗生素治疗后对缺乏共生菌群的小鼠刺激先天免疫防御VRE和KPC的能力。我们相信这些研究将为微生物菌群和肠上皮之间的双向关系提供重要的见解。我们的研究可能为预防或限制由高度耐药细菌引起的感染提供新的方法。公共卫生相关性：在接受抗生素治疗的患者中，高度耐药细菌感染是一个日益普遍的问题。我们已经发现，抗生素通过消灭肠道内的正常细菌，损害了肠道内壁抵抗耐抗生素细菌攻击的能力。我们的实验将确定哪些正常肠道细菌对维持肠道内的抗菌素耐药性很重要，以及哪些哺乳动物分子负责检测肠道内的正常细菌。我们的第三个目标是发现来自细菌的分子是否可以逆转抗生素引起的感染易感性增加。

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.