Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice.
Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice.
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DOI：
10.1371/journal.ppat.1003774
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Schughart K
中科院分区：
文献类型：
--
作者：
Hatesuer B;Bertram S;Mehnert N;Bahgat MM;Nelson PS;Pöhlmann S;Schughart K
每年的流感流行和偶尔的大流行对人类健康构成严重威胁。病毒传播所需的宿主细胞因子而不是细胞生存所需的宿主细胞因子是抗病毒干预新方法的有吸引力的靶点。宿主细胞蛋白酶对流感病毒血凝素(HA)的裂解激活是病毒感染性所必需的。然而，目前还不清楚哪种蛋白水解酶能激活哺乳动物体内的流感病毒。在细胞培养研究中已经确定了几个候选者，导致了流感病毒可以使用多种酶来确保其在宿主中的切割激活的概念。在这里，我们表明，在小鼠中缺失单一的HA激活蛋白水解酶基因TMPRSS2，可以抑制单一碱性H1N1流感病毒的传播，包括2009年大流行的猪流感病毒。肺病理明显减少，突变小鼠的体重减轻、死亡和肺功能受损得到保护。此外，在感染单一碱性H3N2型流感病毒后，TMPRSS2突变体的体重减轻和存活没有野生型小鼠那么严重。正如预期的那样，TMPRSS2缺陷小鼠在感染多基本H7N7甲型流感病毒后，没有受到病毒传播和病理的保护。综上所述，这些结果证实TMPRSS2是一种宿主细胞因子，对病毒传播和单碱基H1N1和H3N2型流感病毒的致病至关重要。季节性流感流行和大流行对人类人口的健康构成严重威胁。对现有抗病毒药物的耐药性经常被观察到。因此，寻找抗病毒治疗的新靶点是当务之急。宿主蛋白酶是处理病毒血凝素所必需的，因此可能是一个合适的干预靶点。在这里，我们报告说，在小鼠中，单个宿主蛋白酶基因TMPRSS2的缺失可以保护宿主免受病毒在感染肺中的传播。TMPRSS2突变小鼠感染H1N1病毒后仅观察到非常轻微的致病作用，感染H3N2病毒后观察到较轻的致病作用。因此，我们的结果表明宿主蛋白酶TMPRSS2可能是抗病毒干预的主要靶点。
Annual influenza epidemics and occasional pandemics pose a severe threat to human health. Host cell factors required for viral spread but not for cellular survival are attractive targets for novel approaches to antiviral intervention. The cleavage activation of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity. However, it is unknown which proteases activate influenza viruses in mammals. Several candidates have been identified in cell culture studies, leading to the concept that influenza viruses can employ multiple enzymes to ensure their cleavage activation in the host. Here, we show that deletion of a single HA-activating protease gene, Tmprss2, in mice inhibits spread of mono-basic H1N1 influenza viruses, including the pandemic 2009 swine influenza virus. Lung pathology was strongly reduced and mutant mice were protected from weight loss, death and impairment of lung function. Also, after infection with mono-basic H3N2 influenza A virus body weight loss and survival was less severe in Tmprss2 mutant compared to wild type mice. As expected, Tmprss2-deficient mice were not protected from viral spread and pathology after infection with multi-basic H7N7 influenza A virus. In conclusion, these results identify TMPRSS2 as a host cell factor essential for viral spread and pathogenesis of mono-basic H1N1 and H3N2 influenza A viruses. Seasonal influenza epidemics and pandemics represent a serious health threat to the human population. Resistance to presently available anti-viral drugs is frequently observed. Therefore, identification of new targets for anti-viral therapy is an urgent need. Host proteases are required for processing of the virus hemagglutinin and may thus represent a suitable target for intervention. Here, we report that the deletion of a single host protease gene, Tmprss2, in mice protects the host against viral spread in infected lungs. Only very mild pathogenesis was observed in Tmprss2 mutant mice after infection with H1N1 virus and less severe pathogenesis was observed after infection with H3N2 virus. Thus, our results suggest that the host protease TMPRSS2 may be a prime target for antiviral intervention.
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6.7
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