Inhibition of PAR2 as therapeutic approach to enhance anti-viral immune responses

抑制 PAR2 作为增强抗病毒免疫反应的治疗方法

基本信息

批准号：
10439793
负责人：
Silvio Antoniak
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439793
关键词：
Adult Age-Years Antiviral Response Blood Coagulation Factor Cardiac Cells Coagulation Process Coxsackie Viruses Development Disease Elderly Epithelial Cells Etiology FDA approved Factor Xa Fibroblasts Goals Heart Host Defense Immune response In Vitro Infection Inflammation Inflammatory Influenza A Virus, H1N1 Subtype Influenza A virus Influenza B Virus Innate Immune Response Interferon-beta Lead Link Lung Lung infections Mediating Modeling Morbidity - disease rate Mus Muscle Cells Myeloid Cells Myocarditis PAR-2 Receptor Pathologic Pathology Pathway interactions Peptide Hydrolases Play Pneumonia Predisposition Preventive Proteinase-Activated Receptors Proteins Pulmonary Pathology Rare Diseases Role Signal Pathway Sudden Death System TLR3 gene Testing Therapeutic Thromboplastin Toll-like receptors Transgenic Mice Trypsin Tryptase United States National Institutes of Health Viral Viral Load result Viral Pneumonia Virus Virus Diseases Virus Replication adaptive immune response antagonist cell type flu improved improved outcome influenza infection influenzavirus inhibitor macrophage mortality mouse model mutant novel novel therapeutics pathogen receptor seasonal influenza viral myocarditis

项目摘要

Viral infections cause considerable morbidity and mortality worldwide. Viruses induce tissue factor (TF) expression in various cell types and this leads to activation of coagulation as part of the innate immune response. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). For instance, the TF:FVIIa:FXa activates PAR2 on a variety of cell types. Besides this, other proteases such as trypsin or tryptase can activate PAR2. Toll-like receptors (TLRs) play a central role in host defense. It has been proposed that TLRs and PARs act as a dual-receptor system to detect pathogens. Viral myocarditis causes up to 20% of sudden death in adults less than 40 years of age. Coxsackievirus B3 (CVB3) is considered to be one of the dominant etiological agents of myocarditis. Influenza A and B virus causes the flu. Influenza virus infects epithelial cells in the lung and in severe cases causes viral pneumonia. The elderly are particularly susceptible to the flu. At present, treatment of myocarditis remains nonspecific and only supportive. Furthermore, optimal IAV treatments are still under development. PAR2 is known to play a major role in multiple inflammatory disorder. In addition, expression and activity of PAR2 activating proteases, such as tryptase and trypsin, has been linked to CVB3 myocarditis and influenza virus infection susceptibility. Recently, we discovered that the PAR2 pathway dampens the innate immune response to CVB3 in mice leading to more pronounced myocarditis. Furthermore, we and others found that PAR2 deficiency was associated with reduced influenza virus infection. At present little is known about the underlying pathologic mechanism of PAR2 in CVB3-induced myocarditis and influenza virus infection. The proposal will elucidate the mechanisms by which PAR2 enhances viral infection using mouse models of CVB3 myocarditis and H1N1 influenza A virus infection. More important, we will test a therapeutic approach by inhibiting FXa or PAR2 to improve the outcome after CVB3 or H1N1 infection. The proposed studies are highly significant because they may elucidate new pathways and treatments to treat viral myocarditis, H1N1 influenza A virus infection and viral infections in general.

病毒感染在全世界造成相当大的发病率和死亡率。病毒诱导组织因子（TF）在各种细胞类型中表达，这导致作为先天免疫一部分的凝血激活回复。凝固蛋白酶通过裂解蛋白酶激活受体 (PAR) 来激活细胞。为了例如，TF:FVIIa:FXa 可激活多种细胞类型上的 PAR2。除此之外，还有其他蛋白酶，例如胰蛋白酶或类胰蛋白酶可以激活 PAR2。 Toll 样受体 (TLR) 在宿主防御中发挥着核心作用。它一直提出 TLR 和 PAR 作为双受体系统来检测病原体。病毒性心肌炎引起 40 岁以下成年人猝死的 20%。柯萨奇病毒 B3 (CVB3) 被认为是一种心肌炎的主要病因。甲型和乙型流感病毒引起流感。流感病毒感染肺部上皮细胞，严重时会引起病毒性肺炎。老年人尤其容易受到影响流感。目前，心肌炎的治疗仍然是非特异性的，仅是支持性的。此外，最优 IAV 治疗仍在开发中。 PAR2 已知在多种炎症中发挥重要作用紊乱。此外，PAR2 激活蛋白酶（如类胰蛋白酶和胰蛋白酶）的表达和活性也与 CVB3 心肌炎和流感病毒感染易感性有关。最近，我们发现， PAR2 通路抑制小鼠对 CVB3 的先天免疫反应，导致更明显的心肌炎。此外，我们和其他人发现 PAR2 缺乏与流感减少有关病毒感染。目前对于 PAR2 在 CVB3 诱导的病理机制中的潜在病理机制知之甚少。心肌炎和流感病毒感染。该提案将阐明 PAR2 的机制使用 CVB3 心肌炎和 H1N1 甲型流感病毒感染的小鼠模型增强病毒感染。更多的重要的是，我们将通过抑制 FXa 或 PAR2 来测试治疗方法，以改善 CVB3 或 H1N1 感染。拟议的研究非常重要，因为它们可能阐明新的途径和用于治疗病毒性心肌炎、H1N1 甲型流感病毒感染和一般病毒感染的治疗方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The coagulation system in host defense.

宿主防御中的凝血系统。

DOI：
发表时间：
2018-07
期刊：
影响因子：
0
作者：
Antoniak; Silvio
通讯作者：
Silvio

Genetic deletion of platelet PAR4 results in reduced thrombosis and impaired hemostatic plug stability.

血小板 PAR4 的基因缺失会导致血栓形成减少和止血塞稳定性受损。

DOI：
发表时间：
2022-02
期刊：
影响因子：
0
作者：
Lee, Robert H;Kawano, Tomohiro;Grover, Steven P;Bharathi, Vanthana;Martinez, David;Cowley, Dale O;Mackman, Nigel;Bergmeier, Wolfgang;Antoniak, Silvio
通讯作者：
Antoniak, Silvio

Protease-activated receptor 4 protects mice from Coxsackievirus B3 and H1N1 influenza A virus infection.

蛋白酶激活受体 4 可保护小鼠免受柯萨奇病毒 B3 和 H1N1 甲型流感病毒感染。

DOI：
10.1016/j.cellimm.2019.103949
发表时间：
2019-10-01
期刊：
Cellular immunology
影响因子：
4.3
作者：
K. Tatsumi;Clare M. Schmedes;E. Reaves Houston;Emily Butler;N. Mackman;S. Antoniak
通讯作者：
S. Antoniak

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus.

呼吸道病毒甲型流感病毒和冠状病毒感染后的组织因子表达、细胞外囊泡和血栓形成。