A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection.
A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection.
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一对旁系同源哺乳动物宿主限制因子形成对抗痘病毒感染的关键宿主屏障
DOI：
10.1371/journal.ppat.1006884
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发表时间：
2018-03
期刊：
影响因子：
6.7
通讯作者：
Xiang Y
中科院分区：
文献类型：
--
作者：
Meng X;Zhang F;Yan B;Si C;Honda H;Nagamachi A;Sun LZ;Xiang Y
宿主限制因子构成了病毒复制的强大屏障，许多病毒已经进化出对抗措施。人SAMD 9是细胞系中痘病毒的肿瘤抑制因子和限制因子，被两类痘病毒蛋白拮抗，以牛痘病毒（VACV）K1和C7为代表。SAMD 9的一个旁系同源物SAMD 9 L也由一些哺乳动物编码，而其他哺乳动物只保留了两个旁系同源物中的一个。在这里，我们表明，SAMD 9 L功能类似于SAMD 9作为一个限制因子，这两个旁系同源物形成了一个关键的宿主屏障，痘病毒必须克服建立感染。在天然缺乏SAMD 9的小鼠中，用病毒抑制剂克服SAMD 9 L限制对于痘病毒复制和发病是必不可少的。虽然缺失K1和C7的VACV（vK 1 L-C7 L-）受到小鼠细胞的限制并且在小鼠中高度减毒，但其复制和毒力在SAMD 9 L-/-小鼠中完全恢复。在人类中，SAMD 9和SAMD 9 L都是痘病毒限制因子，尽管后者在许多细胞类型中需要干扰素诱导。虽然用Crispr-Cas9敲除SAMD 9足以消除许多人细胞中对vKlL-C7 L-的限制，但需要敲除两种旁系同源物以消除干扰素处理的细胞中的限制。这两种旁系同源物都能被来自不同哺乳动物痘病毒的VACV K1、C7和C7同源物拮抗，但小鼠SAMD 9 L对由一组在反刍动物中宿主范围狭窄的痘病毒编码的C7同源物具有抗性，表明SAMD 9/SAMD 9 L基因的宿主种特异性差异是痘病毒跨种传播的障碍。人畜共患病毒感染是对公共卫生的主要威胁。对于许多病毒，病毒进入受体的宿主种属特异性差异是跨种属传播的主要障碍。然而，痘病毒几乎可以进入任何动物细胞。为什么许多痘病毒表现出严格的宿主物种特异性，以及它们需要什么才能跳跃到新的宿主还不清楚。在这里，我们提出的数据表明，SAMD 9和它的paradigm，SAMD 9 L，构成了一个关键的宿主屏障，对痘病毒感染和发病机制。我们还发现SAMD 9/SAMD 9 L存在一些宿主种特异性差异，以及痘病毒在拮抗SAMD 9/SAMD 9 L方面存在一些特异性差异，表明这些差异是痘病毒跨种感染的障碍。这些知识是理解痘病毒宿主范围决定因素的基础。
Host restriction factors constitute a formidable barrier for viral replication to which many viruses have evolved counter-measures. Human SAMD9, a tumor suppressor and a restriction factor for poxviruses in cell lines, is antagonized by two classes of poxvirus proteins, represented by vaccinia virus (VACV) K1 and C7. A paralog of SAMD9, SAMD9L, is also encoded by some mammals, while only one of two paralogs is retained by others. Here, we show that SAMD9L functions similarly to SAMD9 as a restriction factor and that the two paralogs form a critical host barrier that poxviruses must overcome to establish infection. In mice, which naturally lack SAMD9, overcoming SAMD9L restriction with viral inhibitors is essential for poxvirus replication and pathogenesis. While a VACV deleted of both K1 and C7 (vK1L-C7L-) was restricted by mouse cells and highly attenuated in mice, its replication and virulence were completely restored in SAMD9L-/- mice. In humans, both SAMD9 and SAMD9L are poxvirus restriction factors, although the latter requires interferon induction in many cell types. While knockout of SAMD9 with Crispr-Cas9 was sufficient for abolishing the restriction for vK1L-C7L- in many human cells, knockout of both paralogs was required for abolishing the restriction in interferon-treated cells. Both paralogs are antagonized by VACV K1, C7 and C7 homologs from diverse mammalian poxviruses, but mouse SAMD9L is resistant to the C7 homolog encoded by a group of poxviruses with a narrow host range in ruminants, indicating that host species-specific difference in SAMD9/SAMD9L genes serves as a barrier for cross-species poxvirus transmission. Zoonotic viral infections represent a major threat to public health. For many viruses, host species-specific difference in viral entry receptors presents a major hurdle for cross-species transmission. Poxviruses, however, can enter nearly any animal cell. Why many poxviruses show strict host species specificity and what it would take for them to jump to new hosts are less clear. Here, we present data suggesting that SAMD9 and its paralog, SAMD9L, constitute a critical host barrier against poxvirus infection and pathogenesis. We also discovered some host species-specific difference in SAMD9/SAMD9L and some poxvirus-specific difference in antagonizing SAMD9/SAMD9L, suggesting that these differences serve as a barrier for cross-species poxvirus infection. The knowledge is fundamental for understanding the determinants of poxvirus host-range.
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影响因子：
5.5
作者：
Embry, Addie;Meng, Xiangzhi;Cantwell, Angelene;Dube, Peter H.;Xiang, Yan
通讯作者：
Xiang, Yan
DOI：
10.1038/nrmicro1099
发表时间：
2005-03
期刊：
Nature reviews. Microbiology
影响因子：
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作者：
通讯作者：
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通讯作者：
Alman BA
影响因子：
5.4
作者：
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通讯作者：
McFadden, Grant
影响因子：
6.7
作者：
Dhungel P;Cao S;Yang Z
通讯作者：
Yang Z