Host Response and Immunity to Yersenia pestis Infection

派：安德森，黛博拉·M 项目摘要 -- “宿主对鼠疫耶尔森氏菌感染的反应和免疫” 项目摘要 I型干扰素是真核细胞在微生物侵袭细胞内时表达的 它们会诱导出一种强大的抗病毒反应。然而，在细菌感染期间，I型干扰素的表达通常 导致一种病理反应，耗尽所需免疫效应细胞 通行证。我们的实验室已经证明，I型干扰素信号在中性粒细胞衰竭过程中起着重要作用 由鼠疫耶尔森氏菌感染，这是一种革兰氏阴性细菌，是鼠疫的病原体。冒泡的 鼠疫是一种高度传染性的媒介传播疾病，可通过呼吸道和 通过受害者的血管系统传播。败血症和肺炎涉及到迅速 不受控制的全身性炎症反应的发展，导致临床上 耐心，即使接受抗生素治疗也是如此。这三种形式的鼠疫导致了三种主要的 在世界范围内，每年仍造成高死亡率的人类疾病病例，包括 美国西南部的热点地区。到目前为止，很少有人直接或间接地了解宿主的反应 助长了鼠疫的蔓延。这样的反应可能会提出新的战略，以接近后 对症治疗鼠疫和其他急性炎症性疾病。在本申请中，我们建议 研究吞噬细胞与引起炎症的鼠疫杆菌之间的相互作用 在小鼠模型中促进感染进展的反应。我们已经确定了广泛的 在野生型鼠疫杆菌感染过程中被激活的保守的Toll样受体7(TLR7)。激活TLR7 通过鼠疫杆菌触发非规范的信号通路，诱导I型干扰素及其 下游干扰素刺激基因，随后干扰中性粒细胞反应并促进 疾病的发展。在这个项目中，我们的目标是理解这部小说的分子信号事件 途径及其在鼠疫杆菌感染中的作用。我们的长期目标是利用从 该计划旨在更好地了解针对细菌感染的先天免疫反应，并开发针对宿主的 广泛预防急性炎症性传染病的治疗技术，如臭名昭著的 肺鼠疫。

PI: Anderson, Deborah M Project Summary   “Host response and immunity to Yersinia pestis infection” Project Summary Type I interferons are expressed by eukaryotic cells upon intracellular invasion by microbial pathogens and they induce a potent anti-viral response. Yet during bacterial infection, expression of type I IFN often leads to a pathologic response that depletes populations of immune effector cells necessary to mediate clearance. Our laboratory has shown that type I IFN signaling contributes to neutrophil depletion during infection by Yersinia pestis, a Gram-negative bacterium that is the causative agent of the plague. Bubonic plague is a highly infectious vector borne disease that can be transmitted through the respiratory route and disseminated through the vasculature of its victims. Septicemic and pneumonic plagues involve the rapid development of an uncontrolled systemic inflammatory response that causes the clinical collapse of the patient, even with antibiotic treatment. These three forms of plague have been responsible for three major pandemics and still cause annual cases of human disease with a high mortality rate worldwide including a hotspot in the Southwestern United States. To date, little about the host responses that directly or indirectly contribute to the progression of plague. Such responses may present new strategies to approach the post- symptomatic treatment of plague and other acute inflammatory diseases. In this application, we propose to study interactions between phagocytic cells and Y. pestis that are responsible for inducing inflammatory responses that contribute to the progression of infection in a murine model. We have identified the broadly conserved Toll-like receptor 7 (TLR7) as activated during infection by wild type Y. pestis. Activation of TLR7 by Y. pestis triggers a non-canonical signaling pathway that induces the expression of type I IFN and its downstream IFN stimulated genes which subsequently interfere with the neutrophilic response and promote the progression of disease. In this project, we aim to understand the molecular signaling events of this novel pathway and their role during infection with Y. pestis. Our long term goal is to use the information gained from this program to better understand innate immune response to bacterial infection and develop host-targeted therapeutics that broadly protect from acutely inflammatory infectious diseases such as the infamous pneumonic plague.