School of Medicine, University of California Davis, Department of Medial Microbiology and Immunology, Davis, California, United States of America.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Laboratory of Viral Diseases, Bethesda, Maryland, United States of America.
PLoS Pathog. 2021 Jan 14;17(1):e1009183. doi: 10.1371/journal.ppat.1009183. eCollection 2021 Jan.
The antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs from host-restricted poxviruses were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses, a genus with a generally broader host range. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, it is possible that by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.
抗病毒蛋白激酶 R（PKR）是一种重要的宿主限制因子，痘病毒必须克服它才能有效地感染宿主细胞。为了抑制 PKR，许多痘病毒编码了一种真核翻译起始因子 2（eIF2）的α亚基的假底物模拟物，在牛痘病毒中称为 K3。尽管 PKR 与 eIF2α 的相互作用高度保守，但以前已显示来自宿主限制痘病毒的一些 K3 同源物以种特异性方式抑制 PKR。为了更好地定义这种宿主范围功能，我们比较了来自 17 种哺乳动物的 PKR 对亲缘关系密切的正痘病毒 K3 同源物的敏感性，该属的宿主范围通常更广泛。K3 同源物表现出种特异性抑制 PKR 的作用，并表现出三种不同的抑制谱。在某些情况下，来自密切相关物种的 PKR 对 K3 同源物的敏感性表现出明显差异。表达骆驼痘病毒 K3 同源物的牛痘病毒在人源和绵羊细胞中的复制能力比表达牛痘病毒 K3 的病毒高出三个数量级，但两种病毒在牛细胞中的复制能力相当。引人注目的是，在天花病毒和骆驼痘病毒 K3 同源物之间的定点突变实验中，我们发现，为了介导对来自不同宿主物种的 PKR 的增强或减弱抑制作用，需要不同的氨基酸组合。由于影响 K3-相互作用但仍维持 PKR/eIF2α 相互作用的 PKR 可能存在有限数量的可能变化，因此，来自一些潜在新宿主的 PKR 可能偶然对其以前从未遇到过的病毒的 K3 介导的抑制作用敏感。我们得出的结论是，宿主蛋白对病毒抑制的敏感性以及病毒免疫拮抗剂的有效性都不能从其系统发育关系中推断出来，而必须通过实验来确定。
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