Mechanisms of platelet reprogramming during influenza infection

项目总结 流感感染增加了急性心肌梗死(AMI)的发病率，在检测到和 接种疫苗的治疗效益可与目前的急性心肌梗死二级预防疗法相媲美。 血小板是血栓形成的中心血液成分，而不受控制的血小板激活是主要因素 到不稳定冠脉综合征和急性心肌梗死。尽管血栓事件与某些病毒有关 感染--全球病毒进展过程中血小板介导血栓形成的分子机制 流感等感染尚未确诊。这项建议的主要目标是研究 一种以前未被描述的分子机制在血小板中的作用，导致对流感和 最终增加了血栓形成。参照物的机制涉及一种细胞质受体，称为 视黄酸诱导基因-I(RIG-I)受体及其下游信号通路。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 流感感染者。由于血小板是去核的，RIG-I的上调表达提示直接 其前体巨核细胞(MKs)在感染过程中的参与。为此，我们还将研究 巨噬细胞中RIG-I对血小板重编程的贡献，从而导致更有效的病毒反应 血栓形成。考虑到RIG-I信号轴存在于血小板中并被特别上调，我们 假设在感染期间，血小板通过RIG-I信号轴感知流感，从而导致其 激活和MKS对血小板进行重新编程，以增强抗病毒和血栓反应。因此，我们 提出两个具体的研究目标：目的1.确定RIG-I轴的表达和活性 与其抗病毒和/或血栓反应有关的血小板；和目标2.表征MKs的感觉 流感以及这种感知随后如何重新编程RIG-I/MAVS途径，导致增强 抗病毒和血栓前基因的表达。以初步获得的新观察结果为基础 研究，我们提出的研究计划将确定以前未知的信号通路在 血小板，RIG-I/MAV，在介导流感抗病毒和血栓反应中的作用这项提议的结果是 将确定血小板病毒胞浆信号的基本机制，MK对感染的反应，这是如何 协同反应有助于免疫和血栓形成，以及靶向这一途径如何改善 血栓和传染病病理学。

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.