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A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection
PLoS Pathogens ( IF 6.7 ) Pub Date : 2018-02-15 , DOI: 10.1371/journal.ppat.1006884
Xiangzhi Meng , Fushun Zhang , Bo Yan , Chuanping Si , Hiroaki Honda , Akiko Nagamachi , Lu-Zhe Sun , Yan Xiang

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.



中文翻译:

一对副宿主哺乳动物宿主限制因子形成抵抗痘病毒感染的关键宿主屏障

宿主限制因子构成了病毒复制的强大屏障,许多病毒已向其发展了对策。人SAMD9是细胞系中痘病毒的肿瘤抑制因子和限制因子,被痘苗病毒(VACV)K1和C7代表的两类痘病毒蛋白所拮抗。SAMD9的旁系同源物SAMD9L也被某些哺乳动物编码,而其他两个旁系同源物中只有一个被保留。在这里,我们显示SAMD9L的功能与SAMD9类似,作为限制因子,并且这两个旁系同源物形成了痘病毒必须克服以建立感染的关键宿主屏障。在自然缺乏SAMD9的小鼠中,用病毒抑制剂克服SAMD9L的限制对于痘病毒复制和发病机理至关重要。而VACV删除了K1和C7(vK1L - C7L- )由小鼠细胞限制,并且在小鼠中是高度减毒的,它的复制和毒力在被完全恢复SAMD9L / - -小鼠。在人类中,SAMD9和SAMD9L均为痘病毒限制因子,尽管后者需要在许多细胞类型中诱导干扰素。虽然与CRISPR-Cas9 SAMD9的淘汰赛足以废除限制为vK1L - C7L -在许多人细胞中,为了消除干扰素处理细胞中的限制,需要敲除两个旁系同源物。两种旁系同源物均被来自多种哺乳动物痘病毒的VACV K1,C7和C7同源物所拮抗,但小鼠SAMD9L对反刍动物宿主范围狭窄的一组痘病毒编码的C7同源物具有抗性,表明SAMD9 / SAMD9L基因充当跨物种痘病毒传播的障碍。

更新日期:2018-02-16
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