A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection

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.

Lung type II alveolar epithelial cells collaborate with CCR2+inflammatory monocytes in host defense against an acute vaccinia infection in the lungs

“…Through an unbiased genome-wide siRNA 436 screen in human cells, SAMD9 and WDR6 were identified as host restriction factors for vaccinia 437 virus lacking both the C7L and K1L genes (Sivan et al, 2015). C7 can also bind to SAMD9L in 438 mouse, and VACV with both C7L and K1L deletion is highly attenuated in an intranasal infection 439 model, but it gains virulence in SAMD9L -/mice (Meng et al, 2018). The human SAMD9 and 440 murine SAMD9L genes are ISGs (Meng et al, 2018;Tanaka et al, 2010).…”

“…C7 can also bind to SAMD9L in 438 mouse, and VACV with both C7L and K1L deletion is highly attenuated in an intranasal infection 439 model, but it gains virulence in SAMD9L -/mice (Meng et al, 2018). The human SAMD9 and 440 murine SAMD9L genes are ISGs (Meng et al, 2018;Tanaka et al, 2010). Through screening a 441 library of more than 350 human ISGs, overexpression of transcription factor IRF1 was identified 442 to be able to suppress the replication of mutant vaccinia with deletions of C7L and K1L (Meng et 443 al., 2012).…”

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

“…Another example of poxviral species-specificity is found in the poxvirus C7L family, which confers host range function in different poxviruses [37][38][39]. C7 orthologs were shown to bind and inhibit host restriction factors SAMD9 and SAMD9L in a species-specific manner [40][41][42]. Interestingly, this SAMD9/SAMD9L inhibition is mediated by different, unrelated poxvirus proteins such as CPXV CP77 or K1 in some poxviruses.…”

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

“…The use of comparative evolutionary genetic approaches has continued to enrich our understanding of restriction factor biology for more than a decade(24–28). Reciprocal loss of duplicated genes in different species has been shown to contribute to species-specific differences in susceptibility to pathogens(29–32). Similar to reciprocal gene loss, we find that SERINC 2 and SERINC 5 show reciprocal functional adaptation against divergent retroviruses.…”