Host Response and Immunity to Yersenia pestis Infection

宿主对鼠疫耶尔森菌感染的反应和免疫

基本信息

批准号：
9380234
负责人：
DEBORAH M ANDERSON
金额：
$ 37.34万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-08 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9380234
关键词：
Acute Adaptor Signaling Protein Aerosols Antibiotic Therapy Antiviral Response Bacteria Bacterial Infections Breathing Bubonic Plague Cells Clinical Communicable Diseases Data Development Disease Disease Progression Dose Effector Cell Eukaryotic Cell Event Family Generations Genes Goals Gram-Negative Bacteria Growth Human IRF3 gene Immune Immune Evasion Immune response Immunity Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferon Type I Interferons Investigation Laboratories Lead Life Cycle Stages Lung Mediating Modeling Molecular Mus Neutrophil Infiltration Onset of illness Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phagocytes Phenotype Plague Pneumonia Pneumonic Plague Population Receptor Signaling Refractory Regulation Reporting Research Respiratory Tract Infections Role Route Sepsis Septicemic plague Signal Pathway Signal Transduction Southwestern United States Specificity Symptoms Systemic disease Systemic infection TLR7 gene Testing Tissues Toll-like receptors Vector-transmitted infectious disease Virulence Virulence Factors Work Yersinia infections Yersinia pestis cytokine human disease macrophage member microbial mortality mouse model neutrophil novel novel therapeutics pandemic disease pathogen programs respiratory response symptom treatment targeted treatment therapeutic target transcription factor treatment effect treatment strategy vector

项目摘要

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.

PI：Anderson，Deborah M 项目摘要 “宿主的反应和对耶尔森氏念珠菌感染的免疫力” 项目摘要 I型干扰素是由真核细胞在微生物病原体内细胞内侵袭后表达的它们引起潜在的抗病毒反应。然而，在细菌感染期间，经常表达I型导致一种病理反应，该反应耗尽了介导所必需的免疫效应细胞的种群清除。我们的实验室表明，I型IFN信号传导在期间有助于中性粒细胞的部署耶尔森氏菌（Yersinia Pestis）感染，一种革兰氏阴性细菌，是鼠疫的致病药物。泡沫瘟疫是一种高度传染性的载体传播疾病，可以通过呼吸道途径传播通过其可怕的精神的脉管系统传播。农业和肺鼠疫涉及快速发展不受控制的系统性炎症反应，导致导致的临床崩溃患者，即使接受抗生素治疗。这三种形式的瘟疫已造成三个主要大流行病，仍然引起年度人类疾病病例，全球死亡率很高，包括美国西南部的热点。迄今为止，直接或间接的主机回复几乎没有有助于瘟疫的进展。这样的回应可能会提出新的策略来接近邮政鼠疫和其他急性炎症性疾病的有症状治疗。在此应用程序中，我们建议吞噬细胞与Y. 在鼠模型中导致感染进展的反应。我们已经广泛地确定了野生型鼠疫在感染期间激活的保守收费受体7（TLR7）。 TLR7的激活由Y. Pestis触发了一种影响I型IFN及其表达的非典型信号通路下游IFN刺激基因，随后干扰中性粒细胞反应并促进疾病的进展。在这个项目中，我们旨在了解这部小说的分子信号传导事件途径及其在感染Y. Pestis期间的作用。我们的长期目标是使用从中获得的信息该计划更好地了解对细菌感染的先天免疫响应并发展为宿主的靶向广泛可免受急性炎性感染（例如臭名昭著）的治疗剂肺鼠疫。