BACKGROUND:Accumulating evidence implicates the activation of G-protein–coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses.METHODS:Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart.RESULTS:We show that PAR2 activation sustains correlates of severe morbidity—hemodynamic compromise, aggravated hypothermia, and hypoglycemia—despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice.CONCLUSIONS:These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.

中文翻译：

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TF-FVIIa PAR2-β-抑制蛋白信号传导维持柯萨奇病毒 B3 感染小鼠的器官功能障碍

背景：越来越多的证据表明，凝血蛋白酶可激活 G 蛋白偶联 PAR（蛋白酶激活受体），从而调节先天免疫反应。方法：利用 PAR2 信号平台发生遗传改变的小鼠模型，我们探索了以下因素的贡献： PAR2 信号转导柯萨奇病毒 B3 感染，柯萨奇病毒 B3 是一种单链 RNA 病毒，可引起包括心脏在内的多器官组织损伤。 结果：我们发现 PAR2 激活与严重发病率（血流动力学受损、严重低温和低血糖）保持相关性，尽管对病毒。急性病毒性肝损伤后，典型的 PAR2 信号传导会损害与响应病毒 RNA 识别而夸大的 I 型 IFN（干扰素）特征相关的恢复过程。代谢谱与肝组织蛋白质组学相结合显示 PAR2 依赖性肝脏代谢重编程、脂滴储存增加和糖异生。在 β-arrestin 偶联缺陷的 PAR2 C 末端磷酸化突变小鼠中，PAR2 持续的低动力损害、肝脏代谢的重新编程以及不平衡的 IFN 反应都被阻止。因此，上游蛋白酶和免疫代谢反应之间的联系是由细胞内β-抑制蛋白募集介导的偏向 PAR2 信号传导造成的。重要的是，用 NAPc2（线虫抗凝蛋白 c2）阻断能够水解 PAR2 的 TF（组织因子）-FVIIa（凝血因子 VIIa）复合物可减轻病毒触发的病理，重现在蛋白酶裂解抗性 PAR2 小鼠中观察到的效果。 结论：这些数据通过 PAR2-β-arrestin 偶联提供了对 TF-FVIIa 信号轴的深入了解，该信号轴是柯萨奇病毒 B3 感染中炎症触发的组织修复和血流动力学损害的调节因子，并且有可能成为选择性凝血抑制剂的靶标。