Mucosal barrier function during Salmonella infection

描述（由申请人提供）：鼠伤寒沙门菌在免疫正常的个体中引起炎症性腹泻，而在免疫功能低下的患者中引起菌血症，死亡率高。鼠伤寒沙门氏菌引起的早期炎症反应对宿主是有益的，因为它将感染限制在肠道黏膜。然而，这种反应的某些方面也有利于鼠伤寒沙门氏菌，因为它们被利用来成功定植肠道并传播给下一个易感宿主。对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殖肠道，我们知之甚少。我们的长期目标是了解肠黏膜屏障的功能，以及它在系统性感染风险较高的个体中是如何改变的。本应用的目的是调查沙门氏菌发病过程中粘膜炎症的成本和收益。我们的中心假设是细胞因子的一个子集，即TH17细胞因子，既协调了粘膜屏障功能，阻止了鼠伤寒沙门氏菌的全身传播，也协调了鼠伤寒沙门氏菌和其他细菌在炎症肠道中生存的炎症反应。该研究的基本原理是了解粘膜界面上宿主-病原体的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检验我们的假设并实现本申请的目标：1。确定鼠伤寒沙门氏菌感染期间炎症反应的哪些组成部分构成肠道粘膜屏障。我们将研究IL-17和IL-22在鼠伤寒沙门氏菌感染期间协调粘膜屏障的作用。2. 确定鼠伤寒沙门氏菌感染过程中脂钙素-2的诱导机制。我们将研究IL-17和IL-22在诱导肠道抗菌肽脂钙素-2表达中的作用。3. 确定对脂钙素-2的耐药性是否有助于炎症肠道的定植。我们将验证这一假设，即当脂钙素-2表达时，获得iroABCDE铁位点对肠道定植具有优势。

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.