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

• 批准号: 9900742
• 负责人: DEBORAH M ANDERSON
• 金额: $ 36.57万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/9900742
• 关键词: Acute; Adaptor Signaling Protein; Aerosols; Antibiotic Therapy; Antiviral Response; Bacteria; Bacterial Infections; 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; Inhalation; 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; pathogenic microbe; programs; respiratory; response; symptom treatment; systemic inflammatory response; targeted treatment; therapeutic target; transcription factor; treatment effect; treatment strategy; vector

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：安德森，Deborah M 项目摘要   “宿主对鼠疫杆菌感染的反应和免疫力” 项目摘要 I型干扰素在微生物病原体侵入细胞内时由真核细胞表达 它们能诱导出有效的抗病毒反应。然而，在细菌感染过程中，I型IFN的表达通常 导致病理反应，消耗介导免疫应答所必需的免疫效应细胞群， 间隙我们的实验室已经表明，I型IFN信号有助于中性粒细胞耗竭， 鼠疫杆菌感染鼠疫耶尔森氏菌，一种革兰氏阴性细菌，是鼠疫的病原体。淋巴腺 鼠疫是一种传染性极强的病媒传播疾病，可通过呼吸道传播， 通过受害者的脉管系统传播败血症和肺炎瘟疫涉及快速 发展不受控制的全身炎症反应，导致临床崩溃， 患者，即使是抗生素治疗。这三种形式的鼠疫造成了三大主要的 大流行病，每年仍会引起人类疾病病例，死亡率很高，包括 美国西南部的热点地区。到目前为止，很少有关于主机的反应，直接或间接地， 导致了瘟疫的蔓延这种反应可能会提出新的战略，以接近后- 鼠疫和其他急性炎症性疾病的对症治疗。在本申请中，我们建议 研究吞噬细胞与Y.导致炎症的鼠疫 在小鼠模型中，这些反应有助于感染的进展。我们已经确定了广泛的 保守的Toll样受体7（TLR 7）在被野生型Y感染期间被激活。鼠疫TLR 7的激活 由Y.鼠疫触发一种非经典信号通路，诱导I型IFN及其受体的表达。 下游IFN刺激的基因随后干扰嗜酸性反应并促进 疾病的发展在这个项目中，我们的目标是了解这种新的分子信号事件， 途径及其在感染Y.鼠疫我们的长期目标是利用从 该计划旨在更好地了解细菌感染的先天免疫反应，并开发针对宿主的 广泛保护免受急性炎症性感染性疾病的治疗，例如臭名昭著的 肺鼠疫