Regulation Paneth cell defensins by bacterial infection

通过细菌感染调节潘氏细胞防御素

• 批准号: 7066596
• 负责人: Nita H Salzman
• 金额: $ 33.29万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066596
• 关键词: Salmonella; Salmonella typhimurium; bacteria infection mechanism; bacterial disease; cell population study; defensins; host organism interaction; intestinal mucosa; laboratory mouse; mucosal immunity; protein structure function

DESCRIPTION (provided by the applicant): The majority of infections occur via mucosal surfaces, either through breaks in the mucosal barrier or through a pathogen's ability to evade the "front lines" of mucosal defense, the innate immune barrier defenses. Innate defenses prevent the majority of bacteria from damaging or crossing the mucosa, and are integral in signaling the host when this barrier has been breached. Antimicrobial peptides are important components of the mucosal barrier defense. In the small intestinal crypts, highly secretory Paneth cells are the primary source of antimicrobial peptides and other effector molecules. These peptides have demonstrated broad-spectrum antibiotic activity in vitro, and recently have been shown to have a significant role in host defense in vivo. Using Salmonella enterica serovar Typhimurium as a model pathogen we will study Paneth cell (PC) effector response to bacterial infection and the impact of this response on the innate protection of the host. We have found that oral wild type S. typhimurium infection of the mouse results in persistent bacterial colonization of the small intestine, decreased expression and production of PC cryptdins and lysozyme, and alteration of the commensal microbiota. We hypothesize that Paneth cell effector expression can be down-regulated by bacterial infection, and that the subsequent decreases in PC effectors result in changes in the composition of the commensal microbiota and prolonged pathogen colonization. Aim 1 will focus on the physiologic mechanisms of PC effector regulation, using specific Salmonella mutants to identify the role of different routes of host-pathogen interaction and the requirement for specific Salmonella pathogenicity island 1 and 2 effectors. Aim 2 will focus on the biological implications of PC effector reduction with respect to persistent pathogen colonization and impact on the commensal microbiota. The proposed studies should provide greater understanding of the physiologic mechanism of PC effector regulation, the role of PC effectors in innate mucosal host defense, and the interplay between host and pathogen that determine the balance between successful pathogenesis and host survival.

描述（由申请人提供）：大多数感染是通过粘膜表面发生的，要么通过粘膜屏障的断裂或病原体逃避粘膜防御的“前线”的能力，即先天的免疫屏障防御。先天的防御能力阻止大多数细菌损坏或越过粘膜，并且在破坏此障碍时在宿主发出信号中是不可或缺的。抗菌肽是粘膜屏障防御的重要组成部分。在小肠道隐窝中，高度分泌的潘埃特细胞是抗菌肽和其他效应分子的主要来源。这些肽在体外表现出广泛的抗生素活性，最近已显示在体​​内宿主防御中具有重要作用。使用沙门氏菌血清鼠伤寒沙门氏菌作为模型病原体，我们将研究Paneth Cell（PC）效应子对细菌感染的反应以及该反应对宿主先天保护的影响。我们发现，小鼠的口服野生型孢子虫感染会导致小肠的持续细菌定植，降低PC隐脚蛋白和溶菌酶的表达和产生，并改变了Concensal Microtobiota。我们假设Paneth细胞效应子表达可以被细菌感染降低，并且PC效应子随后的降低会导致共生微生物群的组成和延长病原体定殖的变化。 AIM 1将使用特定的沙门氏菌突变体来确定不同宿主 - 病原体相互作用途径的作用以及对特定沙门氏菌致病性岛1和2效应子的需求。 AIM 2将侧重于PC效应子还原对持续的病原体定植和对共生微生物群的影响的生物学意义。拟议的研究应提供对PC效应器调节的生理机制，PC效应子在先天粘膜宿主防御中的作用以及确定成功发病机理和宿主存活之间平衡的宿主与病原体之间的相互作用的作用。