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Abstract：
Influenza A virus (IAV) infection is initiated by hemagglutinin (HA), a glycoprotein exposed on the virion\'s lipid envelope that undergoes cleavage by host cell proteases to ensure membrane fusion, entry into the host cells, and completion of the viral cycle. Transmembrane protease serine S1 member 2 (TMPRSS2) is a host transmembrane protease expressed throughout the porcine airway epithelium and is purported to play a major role in the HA cleavage process, thereby influencing viral pathogenicity and tissue tropism. Pigs are natural hosts of IAV and IAV disease causes substantial economic impact on the pork industry worldwide. Previous studies in mice demonstrated that knocking out expression of TMPRSS2 gene was safe and inhibited the spread of IAV after experimental challenge. Therefore, we hypothesized that knockout of TMPRSS2 will prevent IAV infectivity in the swine model. We investigated this hypothesis by comparing pathogenesis of an H1N1pdm09 virus challenge in wildtype (WT) control and in TMPRSS2 knockout (TMPRSS2 -/-) pigs. We demonstrated that TMPRSS2 was expressed in the respiratory tract in WT pigs with and without IAV infection. No differences in nasal viral shedding and lung lavage viral titers were observed between WT and TMPRSS2 -/- pigs. However, the TMPRSS2 -/- pig group had significantly less lung lesions and significant reductions in antiviral and proinflammatory cytokines in the lung. The virus titer results in our direct challenge model contradict prior studies in the murine animal model, but the reduced lung lesions and cytokine profile suggest a possible role for TMPRSS2 in the proinflammatory antiviral response. Further research is warranted to investigate the role of TMPRSS2 in swine IAV infection and disease.
摘要：
甲型流感病毒（IAV）感染由血凝素（HA）启动，暴露在病毒粒子的脂质包膜上的糖蛋白，通过宿主细胞蛋白酶进行切割以确保膜融合，进入宿主细胞，病毒周期的完成。跨膜蛋白酶丝氨酸S1成员2(TMPRSS2)是在整个猪气道上皮中表达的宿主跨膜蛋白酶,据称在HA裂解过程中起主要作用,从而影响病毒的致病性和组织嗜性。猪是IAV的天然宿主,并且IAV疾病对全世界的猪肉行业造成重大的经济影响。先前在小鼠中的研究表明，敲除TMPRSS2基因的表达是安全的，并且在实验攻击后可以抑制IAV的传播。因此,我们假设在猪模型中敲除TMPRSS2会阻止IAV感染性。我们通过比较野生型（WT）对照和TMPRSS2敲除（TMPRSS2-/-）猪中的H1N1pdm09病毒攻击的发病机理来研究这一假设。我们证明TMPRSS2在有和没有IAV感染的WT猪的呼吸道中表达。在WT和TMPRSS2-/-猪之间没有观察到鼻病毒脱落和肺灌洗病毒滴度的差异。然而,TMPRSS2-/-猪组肺损伤明显减少,肺部抗病毒和促炎细胞因子显著减少.我们的直接攻击模型中的病毒滴度结果与先前在鼠动物模型中的研究相矛盾，但肺损伤和细胞因子谱减少提示TMPRSS2在促炎抗病毒反应中可能发挥作用.需要进一步的研究来研究TMPRSS2在猪IAV感染和疾病中的作用。
