Role of inflammatory monocytes in immunity and host defense against Salmonella

项目总结 炎性单核细胞是一种先天免疫细胞，在免疫和宿主防御中发挥关键作用。他们 起源于骨髓中的祖细胞，在某些病理条件下，可以从 骨髓转化成组织。炎性单核细胞类似于单核髓系来源的抑制细胞， 它们与癌症和最近的感染中的免疫抑制有关；但它们在 宿主对细菌触发物的免疫反应还不是很清楚。为了解决这一知识鸿沟，我们有 我一直在研究炎性单核细胞在沙门氏菌宿主免疫反应中的作用，这些细胞是 在世界范围内导致人类严重发病率和死亡率的病原菌。我们已经出版了 从感染沙门氏菌的小鼠组织中提纯的炎性单核细胞既有保护作用，又有保护作用 可能影响感染结果的免疫抑制特性。此外，我们还拥有 已发表的研究表明，炎性单核细胞为沙门氏菌在炎症患者的管腔内扩张提供了一个利基环境 肠子。我们实验室在本申请中描述的最新工作表明，炎症 单核细胞在持续沙门氏菌感染的早期和晚期控制中起着至关重要的作用。总而言之， 这些已发表和未发表的研究结果证实炎性单核细胞在宿主中起着关键作用。 沙门氏菌的免疫反应。这项应用的目的是定义炎性单核细胞如何 调节宿主与沙门氏菌的相互作用，这是一个对理解沙门氏菌的作用很重要的高影响话题 炎性单核细胞与免疫和宿主防御。我们的中心假设是炎性单核细胞 不仅在诱导沙门氏菌的先天免疫反应中起关键作用，而且在指导过程中也起着关键作用 对沙门氏菌的适应性免疫反应。来测试我们的中心假设的各个方面，并 为了实现我们的目标，我们将1)明确炎性单核细胞如何在糖尿病的发病机制中发挥作用 沙门氏菌引起的结肠炎和2)明确炎性单核细胞如何帮助控制持续性沙门氏菌 感染。由拟议研究产生的概念上的进展有望提供新的、 对炎性单核细胞在免疫和宿主防御中的作用的基本见解，因此将 在这一领域具有强大而持久的影响力。

PROJECT SUMMARY Inflammatory monocytes are innate immune cells that play a key role in immunity and host defense. They originate from progenitors in bone marrow and, under certain pathological conditions, can be recruited from bone marrow into tissues. Inflammatory monocytes resemble mononuclear myeloid-derived suppressor cells, which have been associated with immunosuppression in cancer and, more recently infection; yet their role in host immune responses to bacterial triggers is not well understood. To address this knowledge gap, we have been investigating the role of inflammatory monocytes in the host immune response to Salmonella, which are pathogenic bacteria that cause significant morbidity and mortality in humans worldwide. We have published that inflammatory monocytes purified from tissues of mice infected with Salmonella exhibit both protective and immunosuppressive properties that may influence the outcome of the infection. Furthermore, we have published that inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine. Recent work from our laboratory described in this application has indicated that inflammatory monocytes play an essential role in both early and late control of persistent Salmonella infection. Collectively, these published and unpublished findings establish that inflammatory monocytes play a key role in the host immune response to Salmonella. The objective of this application is to define how inflammatory monocytes modulate host interactions with Salmonella, a high impact topic important for understanding the role of inflammatory monocytes in immunity and host defense. Our central hypothesis is that inflammatory monocytes play a key role not only in the induced innate immune response to Salmonella, but also in directing the course of the adaptive immune response to Salmonella. To test various aspects of our central hypothesis and accomplish our objective, we will 1) define how inflammatory monocytes contribute to the pathogenesis of Salmonella-induced colitis and 2) define how inflammatory monocytes help control persistent Salmonella infection. Conceptual advances resulting from the proposed research are expected to provide new, fundamental insights into the role of inflammatory monocytes in immunity and host defense, and thus will have a strong and sustained influence on the field.