Mucosal barrier function during Salmonella infection

描述（由申请方提供）：鼠伤寒沙门氏菌在免疫功能正常的个体中引起炎性腹泻，而在免疫功能低下的患者中引起菌血症，死亡率高。S.鼠伤寒对宿主是有益的，因为它将感染限制在肠粘膜。然而，这种反应的某些方面对S也是有益的。鼠伤寒沙门氏菌，因为它们被利用来成功地定殖肠道并实现传播到下一个易感宿主。关于哪些粘膜炎症反应构成了系统性沙门氏菌传播的粘膜屏障以及沙门氏菌利用哪些粘膜炎症反应来定植肠道，我们知之甚少。我们的长期目标是了解肠粘膜屏障的功能以及它是如何在全身感染风险较高的个体中改变的。本申请的目的是研究沙门氏菌致病过程中粘膜炎症的成本和效益。我们的中心假设是细胞因子的一个子集，即TH 17细胞因子，协调粘膜屏障功能，防止系统性S。鼠伤寒沙门氏菌传播和炎症反应，利用S。鼠伤寒杆菌和其他细菌在发炎的肠道中存活。拟议研究的基本原理是，了解粘膜界面的宿主-病原体相互作用将导致治疗和预防粘膜表面感染的创新方法，并降低菌血症的风险。我们计划通过追求以下具体目标来测试我们的假设并实现本申请的目标：1.确定在S.鼠伤寒感染我们将研究IL-17和IL-22在S.鼠伤寒感染2.探讨脂质运载蛋白-2在S.鼠伤寒感染我们将研究IL-17和IL-22在诱导肠道中抗菌肽脂质运载蛋白-2-的表达中的作用。3.确定对脂质运载蛋白-2的抗性是否促进发炎肠道的定植。我们将检验以下假设：当脂质运载蛋白-2表达时，iroABCDE iroN基因座的获得赋予肠道定殖的优势。 公共卫生相关性：鼠伤寒沙门氏菌在免疫功能正常的个体中引起炎性腹泻，而在免疫功能低下的患者中，它引起菌血症，死亡率很高。关于哪些粘膜炎症反应构成了系统性沙门氏菌传播的粘膜屏障以及沙门氏菌利用哪些粘膜炎症反应来定植肠道，我们知之甚少。我们的长期目标是了解肠粘膜屏障的功能以及它是如何在全身感染风险较高的个体中改变的。

DESCRIPTION (provided by applicant): Salmonella typhimurium causes inflammatory diarrhea in immunocompetent individuals, while in immunocompromised patients it causes bacteremia with a high mortality rate. The early inflammatory response elicited by S. typhimurium is beneficial to the host because it confines the infection to the gut mucosa. However, aspects of this response are also beneficial to S. typhimurium as they are exploited to successfully colonize the gut and achieve transmission to the next susceptible host. Very little is known about which mucosal inflammatory responses constitute the mucosal barrier to systemic Salmonella dissemination and which are exploited by Salmonella to colonize the gut. Our long-range goal is to understand how the intestinal mucosal barrier functions as well as how it is altered in individuals at higher risk for systemic infections. The objectives of this application are to investigate the costs and benefits of mucosal inflammation during Salmonella pathogenesis. Our central hypothesis is that a subset of cytokines, namely the TH17 cytokines, orchestrates both the mucosal barrier function that prevents systemic S. typhimurium dissemination and the inflammatory responses that are exploited by S. typhimurium and other bacteria to survive in the inflamed gut. The rationale for the proposed research is that understanding the host-pathogen interaction at the mucosal interface will lead to innovative approaches to treat and prevent infections at mucosal surfaces and to reduce the risk of bacteremia. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aims: 1. Determine which components of the inflammatory response constitute the gut mucosal barrier during S. typhimurium infection. We will investigate the role of IL-17 and IL-22 in orchestrating the mucosal barrier during S. typhimurium infection. 2. Determine the mechanism of induction of lipocalin-2 during S. typhimurium infection. We will investigate the role of IL-17 and IL-22 in inducing expression of the antimicrobial peptide lipocalin-2- in the gut. 3. Determine whether resistance to lipocalin-2 facilitates colonization of the inflamed gut. We will test the hypothesis that acquisition of the iroABCDE iroN locus confers an advantage for colonization of the gut when lipocalin-2 is expressed. PUBLIC HEALTH RELEVANCE: Salmonella typhimurium causes inflammatory diarrhea in immunocompetent individuals, while in immunocompromised patients it causes bacteremia with a high mortality rate. Very little is known about which mucosal inflammatory responses constitute the mucosal barrier to systemic Salmonella dissemination and which are exploited by Salmonella to colonize the gut. Our long-range goal is to understand how the intestinal mucosal barrier functions as well as how it is altered in individuals at higher risk for systemic infections.