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

病毒感染在世界范围内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的一部分的凝血激活。 反应凝固蛋白酶通过切割蛋白酶激活受体（PAR）来激活细胞。为 例如，TF：FVIIa：FXa激活多种细胞类型上的PAR 2。除此之外，其他蛋白酶如 胰蛋白酶或类胰蛋白酶可以激活PAR 2。Toll样受体（TLR）在宿主防御中起着重要作用。已经 提出TLR和PAR作为双受体系统检测病原体。病毒性心肌炎会导致 在40岁以下的成年人中，柯萨奇病毒B3（CVB3）被认为是一种 心肌炎的主要病因。甲型和B型流感病毒引起流感。流感病毒感染 肺中的上皮细胞，严重时会引起病毒性肺炎。老年人特别容易受到 对流感的反应目前，心肌炎的治疗仍然是非特异性的，只有支持。此外，最佳 IAV治疗仍在开发中。已知PAR 2在多种炎性细胞因子中起主要作用。 disorder.此外，PAR 2活化蛋白酶如类胰蛋白酶和胰蛋白酶的表达和活性， 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的先天免疫应答，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PAR 2在CVB3诱导的肝细胞凋亡中的病理机制知之甚少。 心肌炎和流感病毒感染。该提案将阐明PAR2 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 重要的是，我们将通过抑制FXa或PAR 2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， 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.