Role of inflammatory monocytes in immunity and host defense against Salmonella

项目摘要 炎性单核细胞是先天性免疫细胞，在免疫和宿主防御中发挥关键作用。他们 来源于骨髓中的祖细胞，并且在某些病理条件下，可以从 骨髓转化为组织炎性单核细胞类似于单核骨髓源性抑制细胞， 它们与癌症中的免疫抑制有关，最近与感染有关;但它们在 宿主对细菌触发物的免疫反应还不清楚。为了弥补这一知识差距，我们 一直在研究炎症单核细胞在宿主对沙门氏菌的免疫反应中的作用， 病原菌在全世界范围内引起人类显著的发病率和死亡率。我们已经发表 从沙门氏菌感染的小鼠组织中纯化的炎性单核细胞既表现出保护性， 可能影响感染结果的免疫抑制特性。此外，我们有 发表了炎性单核细胞为沙门氏菌在发炎的 肠子在本申请中描述的来自我们实验室的最新工作表明，炎症性 单核细胞在持续性沙门氏菌感染的早期和晚期控制中起重要作用。总的来说， 这些已发表和未发表的研究结果表明，炎症单核细胞在宿主中起着关键作用， 对沙门氏菌的免疫反应本申请的目的是确定炎性单核细胞如何 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非常重要的高影响主题。 炎性单核细胞在免疫和宿主防御中的作用。我们的中心假设是炎症单核细胞 不仅在诱导对沙门氏菌的天然免疫应答中起关键作用， 对沙门氏菌的适应性免疫反应为了检验我们中心假设的各个方面， 为了实现我们的目标，我们将：1）确定炎症性单核细胞如何促进炎症的发病机制， 沙门氏菌诱导的结肠炎和2）定义炎症单核细胞如何帮助控制持久性沙门氏菌 感染拟议研究产生的概念进步预计将提供新的， 炎症单核细胞在免疫和宿主防御中的作用的基本见解，因此将有 在球场上有着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 Collectively, these published and unpublished findings establish that inflammatory monocytes play a key role in the host immune response to Salmonella.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.