Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
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DOI：
10.1128/aac.02594-12
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Lucas, Alexandra
中科院分区：
文献类型：
--
作者：
Chen, Hao;Zheng, Donghang;Lucas, Alexandra
致命的病毒感染产生广泛的炎症，伴随血管渗漏、凝血和出血（弥散性血管内凝血[DIC]）、器官衰竭和高死亡率。在凝块形成（血栓形成）和凝块溶解（血栓溶解）级联中的丝氨酸蛋白酶被炎性细胞因子风暴激活，并且还可以诱导全身性炎症，丧失正常丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）调节。粘液瘤病毒分泌一种有效的抗炎丝氨酸蛋白酶抑制剂Serp-1，可抑制凝血因子X（fX）和溶血栓组织型和尿激酶型纤溶酶原激活剂（tPA和uPA），在多种动物模型中具有抗炎活性。纯化的丝氨酸蛋白酶抑制剂显著提高了小鼠γ-疱疹病毒68（MHV 68）感染γ-干扰素受体（IFN-γ R）敲除小鼠（致死性炎性血管炎模型）的存活率。用neuroserpin（一种仅抑制tPA和uPA的哺乳动物丝氨酸蛋白酶抑制剂）治疗MHV 68感染的小鼠无效。Serp-1减少了MHV 68感染小鼠的病毒载量、肺出血以及主动脉、肺和结肠炎症，并且还减少了病毒载量。Neuroserpin抑制MHV 68感染后广泛的免疫脾细胞反应，而Serp-1选择性地增加CD 11 c（+）脾细胞（巨噬细胞和树突状细胞）和减少CD 11b（+）组织巨噬细胞。Serp-1改变了凝血和炎症反应的基因表达，而neuroserpin没有。Serp-1治疗在第二种病毒感染中进行了评估，即野生型BALB/c小鼠中的小鼠适应性扎伊尔埃博拉病毒，具有改善的存活率和减少的组织坏死。总之，用这种独特的粘液瘤病毒衍生的丝氨酸蛋白酶抑制剂治疗抑制由不相关的致死性病毒感染（RNA和DNA病毒）引起的全身丝氨酸蛋白酶和先天性免疫应答，为治疗致死性病毒脓毒症提供了潜在的新治疗方法。
Lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal serine protease inhibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue-and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine gammaherpesvirus 68 (MHV68) infection in gamma interferon receptor (IFN-gamma R) knockout mice, a model for lethal inflammatory vasculitis. Treatment of MHV68-infected mice with neuroserpin, a mammalian serpin that inhibits only tPA and uPA, was ineffective. Serp-1 reduced virus load, lung hemorrhage, and aortic, lung, and colon inflammation in MHV68-infected mice and also reduced virus load. Neuroserpin suppressed a wide range of immune spleen cell responses after MHV68 infection, while Serp-1 selectively increased CD11c(+) splenocytes (macrophage and dendritic cells) and reduced CD11b(+) tissue macrophages. Serp-1 altered gene expression for coagulation and inflammatory responses, whereas neuroserpin did not. Serp-1 treatment was assessed in a second viral infection, mouse-adapted Zaire ebolavirus in wild-type BALB/c mice, with improved survival and reduced tissue necrosis. In summary, treatment with this unique myxomavirus-derived serpin suppresses systemic serine protease and innate immune responses caused by unrelated lethal viral infections (both RNA and DNA viruses), providing a potential new therapeutic approach for treatment of lethal viral sepsis.