Role of inflammatory monocytes in Salmonella-induced colitis

项目总结 肠炎沙门氏菌血清型是导致人类严重发病率和死亡率的病原菌。 全世界。肠胃炎是肠炎沙门氏菌最常见的临床症状。 由非伤寒沙门氏菌血清型引起，如肠沙门氏菌血清型 免疫功能正常人群中的小鼠伤寒杆菌(STM)。作为我们正在进行的研究的一部分，旨在澄清 通过STM建立感染和避免免疫清除的机制，我们开始研究其作用 炎性单核细胞(IM、CD11b+Ly6chi Ly6G-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)的祖细胞， 在一定的病理条件下，可以从骨髓募集到周围组织。我们之前 从感染STM的小鼠组织中提纯的IM既有保护作用，又有保护作用 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在发炎的肠腔内扩张提供了一个利基市场。这些都出版了 我们实验室的研究结果证实IM在STM诱导的结肠炎的发病机制中起关键作用。 最近，我们发现从感染STM的小鼠盲肠中提纯的IM能产生肿瘤坏死 肿瘤坏死因子-α，一种介导STM感染胃肠道早期病理的细胞因子；以及 表达干扰素受体-γ，一种延缓STM诱导的肠道分解的细胞因子 发炎。此应用程序的目的是定义IM如何在STM的发病机制中做出贡献。 诱发性结肠炎，一个高影响力的话题，对于理解IM在免疫和宿主防御中的作用很重要。 我们的中心假设是IM在STM诱导的STM的发病机制中起直接和间接的作用 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)确定 STM感染过程中产生单核细胞趋化因子CCl_2的盲肠细胞类型(S)及测定 肺炎衣原体感染小鼠盲肠组织中IM蓄积是否需要髓系细胞表达CCL2 STM，2)定义IM如何被利用来促进STM在炎症肠腔中的扩张，以及3) 确定IM表达TNFa或Ifngr1是否有助于STM诱导的病理严重程度 结肠炎。拟议研究产生的概念性进展有望提供新的、基本的 对宿主与细菌病原体相互作用的洞察，因此将对 田野。

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.