Role of inflammatory monocytes in Salmonella-induced colitis

炎症单核细胞在沙门氏菌诱导的结肠炎中的作用

• 批准号: 10039094
• 负责人: Adrianus Wilhelmus Maria van der Velden
• 金额: $ 23.59万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039094
• 关键词: Bone Marrow; CC chemokine receptor 2; CCL2 gene; Cecum; Cells; Chemotactic Factors; Chimera organism; Clinical; Colitis; Enterobacteria phage P1 Cre recombinase; Epithelial Cells; Exhibits; GTP-Binding Protein alpha Subunits, Gs; Gastroenteritis; Gastrointestinal tract structure; Gene-Modified; Generations; Goals; Growth; Health; Host Defense; Human; IFNGR1 gene; ITGAM gene; Immune; Immunity; Immunocompetent; Individual; Infection; Inflammatory; Interferon Receptor; Interferons; Intestines; Laboratories; Ligand Binding; Ligands; LoxP-flanked allele; Mediating; Modeling; Morbidity - disease rate; Mus; Myeloid Cells; NOS2A gene; Nitrates; Outcome; Pathogenesis; Pathologic; Pathology; Peripheral; Play; Property; Publishing; Reporter Genes; Research; Resolution; Role; Salmonella; Salmonella enterica; Salmonella typhimurium; Severities; Source; Syndrome; System; TNF gene; Testing; Tissues; beta-Chemokines; cell type; cytokine; gastrointestinal infection; immune clearance; in vivo; inflammatory disease of the intestine; innovation; insight; intestinal epithelium; monocyte; mortality; pathogen; pathogenic bacteria; progenitor; promoter; receptor; recruit

PROJECT SUMMARY Salmonella enterica serovars are pathogenic bacteria that cause significant morbidity and mortality in humans worldwide. Gastroenteritis is the most prevalent of the clinical syndromes associated with Salmonella enterica serovars and is caused by nontyphoidal Salmonella enterica serovars such as Salmonella enterica serovar Typhimurium (STm) in immunocompetent individuals. As part of our ongoing studies aimed at elucidating mechanisms by which STm establish infection and avoid immune clearance, we began to investigate the role of inflammatory monocytes (IM, CD11b+ Ly6Chi Ly6G- cells) in STm-induced colitis. IM are innate immune cells that play a key role in immunity and host defense. IM originate from progenitors in bone marrow (BM) and, under certain pathological conditions, can be recruited from BM into peripheral tissues. We previously published that IM purified from tissues of mice infected with STm exhibit both protective and immunosuppressive properties that may influence the outcome of the infection. Furthermore, we recently published that IM provide a niche for STm expansion in the lumen of the inflamed intestine. These published findings from our laboratory established that IM play a key role in the pathogenesis of STm-induced colitis. Most recently, we have found that IM purified from ceca of mice infected with STm produce tumor necrosis factor (TNF)-α, a cytokine that mediates the early pathology in STm infection of the gastrointestinal tract; and express the receptor for interferon (IFN)-γ, a cytokine that delays resolution of STm-induced intestinal inflammation. The objective of this application is to define how IM contribute to the pathogenesis of STm- induced colitis, a high impact topic important for understanding the role of IM in immunity and host defense. Our central hypothesis is that IM contribute both directly and indirectly to the pathogenesis of STm-induced colitis. To test different aspects of our central hypothesis and accomplish our objective, we will 1) identify the cecal cell type(s) that produce the monocyte chemoattractant CCL2 during STm infection and determine whether Ccl2 expression by myeloid cells is required for the accumulation of IM in ceca of mice infected with STm, 2) define how IM are exploited to promote STm expansion in the lumen of the inflamed intestine, and 3) determine whether Tnfa or Ifngr1 expression by IM contributes to the severity of the pathology of STm-induced colitis. Conceptual advances resulting from the proposed research are expected to provide new, fundamental insights into host interactions with bacterial pathogens and thus will have a strong and sustained influence on the field.

项目摘要 肠道沙门氏菌血清型是导致人类显著发病率和死亡率的病原菌 国际吧胃肠炎是最常见的临床综合征与沙门氏菌肠道 伤寒沙门氏菌是由非伤寒性肠道沙门氏菌血清型引起的，如肠道沙门氏菌血清型 免疫活性个体中的鼠伤寒沙门氏菌（STm）。作为我们正在进行的旨在阐明 STm建立感染和避免免疫清除的机制，我们开始研究STm在感染中的作用。 炎症单核细胞（IM，CD 11b + Ly 6Chi Ly 6 G-细胞）在STm诱导的结肠炎中的表达。IM是先天免疫细胞 在免疫和宿主防御中起着关键作用。IM起源于骨髓（BM）中祖细胞， 在某些病理条件下，可以从BM募集到外周组织中。我们之前 发表了从感染STm的小鼠组织中纯化的IM表现出保护性和 可能影响感染结果的免疫抑制特性。此外，我们最近 发表了IM为STm在发炎肠腔中的扩张提供了一个小生境。这些已发表 我们实验室的发现证实IM在STm诱导的结肠炎的发病机制中起关键作用。 最近，我们发现从STm感染的小鼠盲肠中纯化的IM产生肿瘤坏死， 因子（TNF）-α，一种介导胃肠道STm感染早期病理的细胞因子;和 表达干扰素（IFN）-γ受体，这是一种细胞因子，可延迟STm诱导的肠道炎症消退。 炎症本申请的目的是确定IM如何促进STm的发病机制。 诱导的结肠炎，一个高影响的主题，重要的是了解IM在免疫和宿主防御中的作用。 我们的中心假设是IM直接和间接地参与STm诱导的 结肠炎为了测试我们的中心假设的不同方面并实现我们的目标，我们将1）识别 在STm感染期间产生单核细胞趋化因子CCL 2并决定 骨髓细胞的Ccl 2表达是否是IM在感染的小鼠盲肠中积累所必需的。 STm，2）定义如何利用IM来促进STm在发炎肠的管腔中的扩张，以及3） 确定IM的Tnfa或Ifngr 1表达是否有助于STm诱导的病理学的严重程度。 结肠炎从拟议的研究中产生的概念进步预计将提供新的，基本的， 深入了解宿主与细菌病原体的相互作用，因此将对 外地