Mucosal barrier function during Salmonella infection

沙门氏菌感染期间的粘膜屏障功能

• 批准号: 8414822
• 负责人: Manuela Raffatellu
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414822
• 关键词: Acquired Immunodeficiency Syndrome; Africa South of the Sahara; Anti-Retroviral Agents; Bacteremia; Bacteria; Bacterial Infections; Benign; Blood; Costs and Benefits; Data; Defect; Diarrhea; Gastroenteritis; Goals; Immune response; Immunocompetent; Immunocompromised Host; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-17; Intestinal Mucosa; Intestines; Iron; Lead; Life; Localized Disease; Macaca mulatta; Mediating; Mucositis; Mucous Membrane; Mus; Outcome; Outcome Study; Pathogenesis; Patients; Research; Resistance; Risk; Role; SIV; Salmonella; Salmonella infections; Salmonella typhimurium; Serotyping; Surface; Systemic infection; Testing; United States; Western Europe; Work; antimicrobial; antimicrobial peptide; arm; base; chemokine; cytokine; expectation; high risk; innovation; interleukin-22; mortality; neutrophil; pathogen; prevent; public health relevance; response; secondary immune deficiency; transmission process; trend

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.

描述（由申请人提供）：鼠伤寒沙门氏菌在免疫能力的个体中引起炎症性腹泻，而在免疫功能低下的患者中，它会导致较高的死亡率菌血症。鼠伤寒链球菌引起的早期炎症反应对宿主有益，因为它将感染局限于肠粘膜。但是，这种反应的各个方面也对鼠伤寒沙门氏菌也有益，因为它们被利用以成功地定居肠道并将其传播到下一个易感宿主。关于哪种粘膜炎症反应构成了全身沙门氏菌传播的粘膜屏障，而沙门氏菌剥削了哪种粘膜障碍，以构成肠道的粘膜屏障。我们的远程目标是了解肠粘膜屏障功能以及如何改变系统性感染风险的个体的改变。该应用的目标是研究沙门氏菌发病机理期间粘膜炎症的成本和收益。我们的中心假设是，一部分细胞因子（即Th17细胞因子）策划了防止系统性的伤寒链霉菌传播的粘膜屏障功能，以及由S. typhimurium链球菌和其他细菌所利用的炎症反应，以在发炎的肠道中生存。拟议的研究的理由是，了解粘膜界面处的宿主 - 病原体相互作用将导致创新的方法来治疗和预防粘膜表面感染并降低菌血症的风险。我们计划通过追求以下特定目的来检验我们的假设并实现本应用的目标：1。确定炎症反应的哪些组成部分构成了鼠伤寒沙门氏菌感染期间的肠粘膜屏障。我们将研究IL-17和IL-22在伤寒链霉菌感染期间策划粘膜屏障中的作用。 2。确定鼠伤寒链霉菌感染期间脂肪蛋白-2的诱导机理。我们将研究IL-17和IL-22在诱导肠道中抗菌肽Lipocalin-2-诱导表达的作用。 3。确定对Lipocalin-2的耐药性是否促进发炎的肠道定植。我们将检验以下假设：在表达Lipocalin-2时，iroabcde铁基因座的采集赋予了肠道定殖的优势。