Rare variant MX1 alleles increase human susceptibility to zoonotic H7N9 influenza virus
Rare variant MX1 alleles increase human susceptibility to zoonotic H7N9 influenza virus
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DOI：
10.1126/science.abg5953
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发表时间：
2021-08-20
期刊：
影响因子：
56.9
通讯作者：
Shu, Yuelong
中科院分区：
文献类型：
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作者：
Chen, Yongkun;Graf, Laura;Shu, Yuelong
人畜共患禽流感A病毒（IAV）感染是罕见的。尚未观察到这些IAV在人类之间的持续传播，这表明宿主基因的作用。我们使用全基因组测序来比较禽IAV H7N9患者与健康对照，并观察到H7N9感染与MX1基因中罕见的杂合单核苷酸变异之间的强相关性。MX1编码粘病毒抗性蛋白A（MxA），一种干扰素诱导的抗病毒鸟苷三磷酸酶，已知可控制转基因小鼠中的IAV感染。在转染的人类细胞系中，鉴定的大多数MxA变体丧失了抑制禽类IAV（包括H7N9）的能力。几乎所有的失活MxA变体对野生型MxA的抗病毒功能都产生显性负效应，表明杂合子携带者中存在MxA无效表型。我们的研究为基于MX1的抗病毒防御在控制人类人畜共患IAV感染中的关键作用提供了遗传证据。
Zoonotic avian influenza A virus (IAV) infections are rare. Sustained transmission of these IAVs between humans has not been observed, suggesting a role for host genes. We used whole-genome sequencing to compare avian IAV H7N9 patients with healthy controls and observed a strong association between H7N9 infection and rare, heterozygous single-nucleotide variants in the MX1 gene. MX1 codes for myxovirus resistance protein A (MxA), an interferon-induced antiviral guanosine triphosphatase known to control IAV infections in transgenic mice. Most of the MxA variants identified lost the ability to inhibit avian IAVs, including H7N9, in transfected human cell lines. Nearly all of the inactive MxA variants exerted a dominant-negative effect on the antiviral function of wild-type MxA, suggesting an MxA null phenotype in heterozygous carriers. Our study provides genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic IAV infections in humans.