Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.
Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.
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DOI：
10.1371/journal.ppat.1003279
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Schwemmle M
中科院分区：
文献类型：
--
作者：
Mänz B;Dornfeld D;Götz V;Zell R;Zimmermann P;Haller O;Kochs G;Schwemmle M
干扰素诱导的动力蛋白样MxA GTPase限制甲型流感病毒的复制。我们在大流行毒株A/Brevig Mission/1/1918（1918）和A/Hamburg/4/2009 （pH1N1）的核蛋白（NP）中发现了赋予MxA抗性的适应性突变。这些耐药相关氨基酸在两种菌株之间存在差异，但在NP的体域形成相似的离散表面暴露簇，表明MxA抗性是独立进化的。1918年的群集在所有季节性流感病毒的后代株中都是保守的。将该簇引入对MxA敏感的流感病毒A/Thailand/1(KAN-1)/04 （H5N1）的NP中，导致MxA抗性增加，同时病毒复制适合度降低。相反，在pH1N1 NP中引入mxa敏感氨基酸可促进mx阴性细胞中的病毒生长。我们的结论是，人MxA是抵御人畜共患禽流感病毒传入的屏障，应仔细监测病毒NP的适应性突变。源自禽类或猪的甲型流感病毒偶尔会进入人群，但不会在个体之间传播。然而，在极少数情况下，它们在人类身上建立了新的病毒谱系。入侵病毒克服物种屏障的机制尚不清楚，但需要对新宿主进行多重适应。令人惊讶的是，人们对克服内在和先天宿主防御系统限制因素的适应性突变知之甚少。在这项研究中，我们在大流行毒株A/Brevig Mission/1/1918和A/Hamburg/4/2009中发现了适应性突变，这些突变赋予了对干扰素诱导的抗病毒因子MxA的抗性，MxA是一种动力蛋白样的大GTPase，可识别传入的病毒核衣壳并阻断其功能。抗性增强突变改变了病毒核蛋白中的几个氨基酸，而核蛋白是核衣壳的主要成分。这些突变足以在mx阳性小鼠模型中增加禽流感病毒株的致病性。有趣的是，在流行的禽流感毒株中，与耐药性相关的氨基酸是反选择的，因为它们损害了病毒复制的一般适应性。目前的数据表明，先天免疫因子MxA对甲型流感病毒的人畜共患引入提供了屏障，必须仔细监测核蛋白的适应性突变。
The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored. Influenza A viruses of avian or swine origin sporadically enter into the human population but do not transmit between individuals. In rare cases, however, they establish a new virus lineage in humans. The mechanisms by which invading viruses overcome the species barrier are not well understood, but multiple adaptations to the new host are required. Surprisingly little is known about adaptive mutations that overcome restriction factors of the intrinsic and innate host defense system. In this study, we have identified adaptive mutations in pandemic strains A/Brevig Mission/1/1918 and A/Hamburg/4/2009 that confer resistance to the interferon-induced antiviral factor MxA which is a dynamin-like large GTPase that recognizes the incoming viral nucleocapsids and blocks their function. The resistance-enhancing mutations changed several amino acids in the viral nucleoprotein which is the main nucleocapsid component. These mutations were sufficient to increase the pathogenicity of an avian influenza virus strain in a Mx-positive mouse model. Interestingly, the resistance-associated amino acids are counter-selected in circulating avian influenza strains, because they compromise general viral replication fitness. The present data indicate that the innate immunity factor MxA provides a barrier against zoonotic introduction of influenza A viruses and that adaptive mutations in the nucleoprotein must be carefully monitored.
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