Equine Mx1 Restricts Influenza A Virus Replication by Targeting at Distinct Site of its Nucleoprotein

Abstract

Interferon-mediated host factors myxovirus (Mx) proteins are key features in regulating influenza A virus (IAV) infections. Viral polymerases are essential for viral replication. The Mx1 protein has been known to interact with viral nucleoprotein (NP) and PB2, resulting in the influence of polymerase activity and providing interspecies restriction. The equine influenza virus has evolved as an independent lineage to influenza viruses from other species. We estimated the differences in antiviral activities between human MxA (huMxA) and equine Mx1 (eqMx1) against a broad range of IAV strains. We found that huMxA has antiviral potential against IAV strains from non-human species, whereas eqMx1 could only inhibit the polymerase activity of non-equine species. Here, we demonstrated that NP is the main target of eqMx1. Subsequently, we found adaptive mutations in the NP of strains A/equine/Jilin/1/1989 (H3N8JL89) and A/chicken/Zhejiang/DTID-ZJU01/2013 (H7N9ZJ13) that confer eqMx1 resistance and sensitivity respectively. A substantial reduction in Mx1 resistance was observed for the two mutations G34S and H52N in H3N8JL89 NP. Thus, eqMx1 is an important dynamic force in IAV nucleoprotein evolution. We, therefore, suggest that the amino acids responsible for Mx1 resistance should be regarded as a robust indicator for the pandemic potential of lately evolving IAVs.

Proteomic analysis reveals zinc-finger CCHC-type containing protein 3 as a factor inhibiting virus infection by promoting innate signaling

“…Next, we aimed to uncover the underlying mechanisms by which ZCCHC3 inhibits H9N2 infection. In recent years, accumulating evidence showed that the host factors, including Mx1 and ISG20 could markedly inhibit influenza virus replication through modulating innate immune response ( Fatima et al., 2019 ; Qu et al., 2016 ). Hence, we investigated whether ZCCHC3 affected innate signaling.…”

Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs

“…The Mx (myxovirus) gene encoding an ~75 kDa protein was the first ISG to be discovered to confer resistance to influenza virus infection [ 8 , 9 , 10 , 11 , 12 ]. Except for chickens [ 13 , 14 , 15 , 16 ], Mx proteins in the majority of influenza virus hosts, e.g., humans [ 17 ], pigs [ 18 , 19 ], and horses [ 20 ], exhibit antiviral activity. Mx proteins are dynamin-like GTPases [ 21 , 22 , 23 ], which oligomerize into ring-like structures [ 24 , 25 , 26 , 27 , 28 ] and target influenza virus vRNPs to exert their antiviral function [ 29 , 30 ].…”

“…Mx proteins are dynamin-like GTPases [ 21 , 22 , 23 ], which oligomerize into ring-like structures [ 24 , 25 , 26 , 27 , 28 ] and target influenza virus vRNPs to exert their antiviral function [ 29 , 30 ]. Human Mx protein interacts with viral NP and PB2 to sense and sequester the incoming vRNPs in the cytoplasm and inhibit their nuclear import and subsequent viral RNA transcription and replication [ 20 , 29 , 30 , 31 , 32 , 33 ]. Human Mx protein is a barrier to the zoonotic transmission of avian influenza viruses and recently discovered bat influenza viruses to humans [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

Anti-influenza A virus restriction factors that shape the human species barrier and virus evolution

“…Likewise, Mx1 proteins are part of the species barrier against IAVs in other mammalian species. Equine Mx1 blocks avian and human IAVs, whereas equine IAVs have escaped from restriction [ 12 ]. Similarly, porcine Mx1 inhibits avian IAVs, but is only weakly active against swine or human IAVs [ 11 , 13 ].…”