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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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Meng X, Zhang F, Yan B, Si C, Honda H, Nagamachi A, Sun LZ, Xiang Y,


Meng X, Zhang F, Yan B, Si C, Honda H, Nagamachi A, Sun LZ, Xiang Y, (click to view)

Meng X, Zhang F, Yan B, Si C, Honda H, Nagamachi A, Sun LZ, Xiang Y,

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PLoS pathogens 2018 02 1514(2) e1006884 doi 10.1371/journal.ppat.1006884

Abstract

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.

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