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

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) 在不同类型的细胞中表达，这导致凝血的激活作为先天免疫的一部分 回应。凝血酶通过裂解酶激活受体(PARs)来激活细胞。为 实例中，Tf：FVIIa：FXA在各种细胞类型上激活PAR2。除此之外，其他的蛋白酶，如 胰酶或胰酶可以激活PAR2。Toll样受体在宿主防御中起着核心作用。一直以来 提出了TLRs和PARS作为检测病原体的双受体系统。病毒性心肌炎导致UP 到20%的猝死发生在40岁以下的成年人中。柯萨奇病毒B3(CVB3)被认为是 心肌炎的主要病原体。甲型和乙型流感病毒引起流感。流感病毒感染 肺部和严重病例中的上皮细胞会导致病毒性肺炎。老年人特别容易受到影响 到了流感。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疗法仍在开发中。已知PAR2在多发性炎症中起主要作用 无序。此外，PAR2激活蛋白水解酶的表达和活性，如胰蛋白酶和胰蛋白酶， 与CVB3心肌炎和流感病毒感染易感性有关。最近，我们发现 PAR2途径抑制小鼠对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缺乏与流感的减少有关 病毒感染。目前，在CVB3诱导下，PAR2的潜在病理机制尚不清楚 心肌炎和流感病毒感染。该提案将阐明PAR2通过什么机制 利用CVB3型心肌炎和甲型H1N1流感病毒感染的小鼠模型增强病毒感染。更多 重要的是，我们将测试一种治疗方法，通过抑制FXA或PAR2来改善CVB3或 H1N1感染。拟议的研究具有非常重要的意义，因为它们可能阐明新的途径和 治疗病毒性心肌炎、甲型H1N1流感病毒感染和一般病毒感染。

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.