Mechanisms of platelet reprogramming during influenza infection

流感感染期间血小板重编程的机制

• 批准号: 10451515
• 负责人: Milka Koupenova
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451515
• 关键词: Acute; Acute myocardial infarction; Address; Adhesions; Affect; Antiviral Response; Biology; Blood; Blood Platelets; Bone Marrow; Cardiovascular Diseases; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Collaborations; Communicable Diseases; Consultations; Coronary; Cytoplasmic Receptors; Detection; Diagnostic; Disease; Event; Functional disorder; Generations; Genes; Goals; Human; Immune response; Immunity; Incidence; Incubated; Individual; Infection; Influenza; Knock-out; Lead; Lung; Mediating; Megakaryocytes; Messenger RNA; Mitochondria; Modeling; Molecular; Mus; Nature; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Pharmacology; Phenotype; Platelet Activation; Principal Investigator; Protein Analysis; Proteins; RNA; RNA Viruses; Receptor Signaling; Regulation; Research; Research Proposals; Role; Secondary Prevention; Signal Pathway; Signal Transduction; Signaling Protein; Syndrome; TLR7 gene; Therapeutic; Thrombosis; Time; Tretinoin; Up-Regulation; Vaccination; Viral; Viral Proteins; Viremia; Virion; Virus Diseases; antagonist; burden of illness; experience; flu; immune function; in vivo; influenza infection; mRNA Expression; mouse model; negative affect; novel; receptor; response; therapeutic target; therapy design; thrombotic; vaccine efficacy; vascular injury; viral RNA

PROJECT SUMMARY Influenza infection increases the incidence of acute MI (AMI) within the first 7 days after detection and the therapeutic benefit of vaccination is comparable to current therapies for secondary prevention of AMI. Platelets are the blood component central to thrombosis and uncontrolled platelet activation is a major contributor to unstable coronary syndromes and AMI. Although thrombotic events have been associated with some viral infections, the molecular mechanisms underlining platelet mediated thrombosis during progression of global viral infection such as influenza have not been established. The major objective of this proposal is to examine the role of a previously undescribed molecular mechanism in platelets that leads to sensing of influenza and ultimately increased thrombosis. The mechanism of reference involves a cytoplasmic receptor known as the retinoic acid-inducible gene-I (RIG-I) receptor and its downstream signaling cascade. Preliminary results show that RIG-I and proteins related to RIG-I molecular signaling become specifically upregulated in platelets from influenza infected patients. Since platelets are anucleated the upregulated expression of RIG-I suggests direct involvement of their precursors the megakaryocytes (MKs) during infection. For that purpose, we will also study the contribution of RIG-I in MKs to platelet reprogramming toward more efficient viral response that may lead to thrombosis. Considering that the RIG-I-signaling axis is present in platelets and specifically upregulated, we hypothesize that during infection, platelets sense influenza through the RIG-I signaling axis leading to their activation and MKs reprogram platelets toward an increased antiviral and thrombotic response. Thus, we propose two specific aims of research: Aim 1. To determine the expression and activity of the RIG-I axis in platelets with respect to their antiviral and/or thrombotic responses; and Aim 2. To characterize how MKs sense influenza and how this sensing subsequently reprograms the RIG-I/MAVS pathway, leading to enhanced expression of antiviral and prothrombotic genes. Building upon novel observations obtained in preliminary studies, our proposed research plan will determine the role of a previously unknown signaling pathway in platelets, RIG-I/MAVS, in mediating influenza antiviral and thrombotic responses. The outcome of this proposal will define the fundamental mechanisms of platelet viral cytosolic signaling, MK response to infection, how this synergistic response contributes to immunity and thrombosis, and how targeting this pathway could ameliorate thrombotic and infectious disease pathologies.

项目摘要 流感感染会增加检测后前7天内急性心肌梗死（AMI）的发病率， 疫苗接种的治疗益处与目前用于AMI二级预防的疗法相当。 血小板是血栓形成的主要血液成分，不受控制的血小板活化是主要原因 不稳定冠状动脉综合征和急性心肌梗死。尽管血栓形成事件与一些病毒性疾病有关， 感染，全球病毒性疾病进展期间血小板介导血栓形成的分子机制 诸如流感感染尚未确定。这项建议的主要目的是研究 一种以前未描述的分子机制在血小板中的作用，导致流感的感知， 最终增加血栓形成。参照机制涉及一种称为 视黄酸诱导基因-I（RIG-I）受体及其下游信号级联。初步结果显示 RIG-I和与RIG-I分子信号相关的蛋白质在血小板中特异性上调， 流感患者。由于血小板是无核的，RIG-I的表达上调提示直接的血小板活化。 在感染过程中，它们的前体巨核细胞（MK）的参与。为此，我们还将研究 MK中RIG-I对血小板重编程朝向更有效的病毒应答的贡献， 血栓形成考虑到RIG-I-信号轴存在于血小板中并且特异性上调，我们 假设在感染期间，血小板通过RIG-I信号传导轴感知流感，导致其 活化和MK重编程血小板，使抗病毒和血栓形成反应增加。因此我们 提出了两个具体的研究目标：目标1。为了确定RIG-I轴的表达和活性， 血小板的抗病毒和/或血栓形成反应;和目的2.为了描述MK如何感知 流感以及这种传感随后如何重新编程RIG-I/MAVS途径，导致增强的 抗病毒和促血栓形成基因的表达。根据初步研究中获得的新观察结果， 研究中，我们提出的研究计划将确定一个以前未知的信号通路的作用， 血小板，RIG-I/MAVS，在介导流感抗病毒和血栓形成反应。这一提议的结果 将定义血小板病毒胞质信号的基本机制，MK对感染的反应， 协同反应有助于免疫和血栓形成，以及如何靶向这一途径可以改善 血栓形成和感染性疾病病理学。