Mucosal barrier function during Salmonella infection

描述(申请人提供)：鼠伤寒沙门氏菌在免疫能力正常的人中引起炎症性腹泻，而在免疫功能低下的患者中引起菌血症，死亡率很高。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粘膜上。然而，这种反应的某些方面对鼠伤寒沙门氏菌也是有利的，因为它们被利用来成功地定植肠道并实现向下一个敏感宿主的传播。关于哪些粘膜炎症反应构成了阻止沙门氏菌系统性传播的粘膜屏障，以及沙门氏菌利用哪些粘膜炎症反应来定植肠道，人们知之甚少。我们的长期目标是了解肠道粘膜屏障是如何发挥作用的，以及在系统性感染风险较高的个人中，它是如何改变的。这项应用的目的是调查沙门氏菌致病过程中粘膜炎症的成本和收益。我们的中心假设是，一组细胞因子，即TH17细胞因子，既协调了防止鼠伤寒沙门氏菌全身传播的粘膜屏障功能，也协调了被鼠伤寒沙门氏菌和其他细菌利用以在炎症的肠道中生存的炎症反应。这项拟议研究的基本原理是，了解宿主和病原体在粘膜界面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特定目标来验证我们的假设并实现这一应用的目标：1.确定在鼠伤寒沙门氏菌感染过程中，炎症反应的哪些成分构成了肠道粘膜屏障。我们将研究IL-17和IL-22在鼠伤寒沙门氏菌感染过程中对黏膜屏障的调节作用。2.确定鼠伤寒沙门氏菌感染过程中Lipocalin-2的诱导机制。我们将研究IL-17和IL-22在诱导肠道抗菌肽Lipocalin-2-表达中的作用。3.确定对Lipocalin-2的抗药性是否有助于炎症肠道的定植。我们将检验这样的假设，即当Lipocalin-2表达时，获得iroABCDE铁基因位点有利于肠道的定植。 公共卫生相关性：鼠伤寒沙门氏菌在免疫能力正常的人中会引起炎症性腹泻，而在免疫功能低下的患者中会导致菌血症，死亡率很高。关于哪些粘膜炎症反应构成了阻止沙门氏菌系统性传播的粘膜屏障，以及沙门氏菌利用哪些粘膜炎症反应来定植肠道，人们知之甚少。我们的长期目标是了解肠道粘膜屏障是如何发挥作用的，以及在系统性感染风险较高的个人中，它是如何改变的。

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.