Innate Immunity & Hemorrhagic Fever Viruses

先天免疫

• 批准号: 7645348
• 负责人: Robert William Finberg
• 金额: $ 68.16万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645348
• 关键词: Acute; Affect; Antigen Presentation; Arenavirus; B-Lymphocytes; Biology; Bioterrorism; Blood Proteins; CD14 gene; Cell Line; Cells; Cessation of life; Chemicals; Collaborations; Data; Development; Disease; Dose; Ebola virus; Engineering; Event; Fever; Filovirus; Functional disorder; Glycoproteins; Human; Human Cell Line; Hypotension; IL8 gene; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response Pathway; Knockout Mice; Lead; Leukopenia; Lymphocytic choriomeningitis virus; Mediating; Meningitis; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pattern Recognition; Pattern recognition receptor; Phase; Preclinical Drug Evaluation; Production; Proteins; Rate; Reporter; Role; Running; Screening procedure; Sepsis; Series; Shock; Signal Transduction Pathway; T-Lymphocyte; TLR1 gene; TLR3 gene; TLR4 gene; TLR6 gene; Testing; Therapeutic; Thrombocytopenia; Toll-Like Receptor 2; Toll-like receptors; Vaccines; Variant; Viral Hemorrhagic Fevers; Viral Proteins; Virus; Virus Diseases; Work; acquired immunity; cytokine; hemorrhagic fever virus; in vivo; macrophage; mortality; novel; novel therapeutics; receptor; research study; response; small molecule; small molecule libraries

This project will examine the role of the innate immune system in the pathophysiology of the viral hemorrhagic fevers. Two viruses which are potential agents of bioterrorism, will be studied: 1) Ebola virus, a filovirus, which induces an acute illness characterized by fever, leucopenia, shock, and death, and 2) Lymphocytic Choriomeningitis Virus LCMV an arenavirus which causes an illness characterized by leucopenia and thrombocytopenia in mice and meningitis in humans. The high mortality rate associated with Ebola infection has-been demonstrated to be directly associated with cytokine release which occurs after viral infection of macrophages. The mechanism by which Ebola induces this cytokine response will be defined and compounds will be screened for their ability to inhibit this activity. Preliminary data indicate a major role for Toll Like Receptor 2 (TLR-2) and CD14 in the cytokine response to LCMV. TLR-2 and CD14 are pattern recognition proteins whose role in bacterial sepsis has been recently defined. Both have also been associated with the immune responses to viruses. Using transfected cell lines and available knockout mice the mechanism by which these proteins affect both initial induction of cytokines as well as the subsequent immune responses to LCMV and Ebola virus will be defined. The specific TLRs (and other "pattern recognition proteins") involved in these responses as well as their interactions will be studied. The effect of these early recognition events on long-term Band T cell immunity will be investigated. These studies will result in a better understanding of the role that the innate immune system has in mediating the pathophysiology of hemorrhagic fever viruses and should lead to new therapeutic approaches to these diseases.

该项目将研究先天免疫系统在病毒生理学中的作用 出血发烧。将研究两种是生物恐怖的潜在药物的病毒：1）埃博拉病毒，A filevirus诱导以发烧，白细胞减少，休克和死亡为特征的急性疾病，2） 淋巴细胞绒毛膜炎病毒病毒LCMV ARANAVIRUS，导致疾病为特征 小鼠和人脑膜炎的白细胞减少和血小板减少症。与 埃博拉病毒感染已证明与细胞因子释放直接相关，后者发生在病毒之后 巨噬细胞的感染。埃博拉诱导这种细胞因子反应的机制，并 将筛选化合物抑制这种活性的能力。初步数据表明 在细胞因子对LCMV的反应中，收费类似于受体2（TLR-2）和CD14。 TLR-2和CD14是模式 最近定义了在细菌败血症中作用的识别蛋白。两者也有关联 对病毒的免疫反应。使用转染的细胞系和可用的基因敲除小鼠 这些蛋白质影响细胞因子的初始诱导以及随后的机制 将定义对LCMV和埃博拉病毒的免疫反应。特定的TLR（以及其他“模式） 将研究参与这些反应及其相互作用的识别蛋白”。 这些关于长期带T细胞免疫力的早期识别事件将被研究。这些研究会 可以更好地理解先天免疫系统在调解介导的作用 出血热病毒的病理生理学，应导致这些新的治疗方法 疾病。