Anti-Influenza A Virus Activities of Type I/III Interferons-Induced Mx1 GTPases from Different Mammalian Species

Van, Phai Dam; Desmecht, Daniël; Garigliany, Mutien-Marie; Anh, Dao Bui Tran; Laere, Anne-Sophie Van

doi:10.1089/jir.2018.0157

Cited by 9 publications

(13 citation statements)

References 36 publications

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“…To evaluate this astonishing specificity, we tested a broader collection of MX1 proteins from different species which have been shown to be antivirally active against influenza A viruses. We cloned the cDNA of eight different mammalian MX1 homologs from bat [48], ferret [49], dog [50], swine [44], cow [51], horse [52], orangutan, and African green monkey [43] into identical expression vectors and determined their activity in the polymerase reconstitution assays of SiAr126 and JOSV. Interestingly, the SiAr126 activity was only restricted by the co-expression of human MxA, the humanoid orangutan MX1 and equine MX1.…”

Section: Plos Pathogensmentioning

confidence: 99%

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

et al. 2020

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Infections with emerging and re-emerging arboviruses are of increasing concern for global health. Tick-transmitted RNA viruses of the genus Thogotovirus in the Orthomyxoviridae family have considerable zoonotic potential, as indicated by the recent emergence of Bourbon virus in the USA. To successfully infect humans, arboviruses have to escape the restrictive power of the interferon defense system. This is exemplified by the high sensitivity of thogotoviruses to the antiviral action of the interferon-induced myxovirus resistance protein A (MxA) that inhibits the polymerase activity of incoming viral ribonucleoprotein complexes. Acquiring resistance to human MxA would be expected to enhance the zoonotic potential of these pathogens. Therefore, we screened a panel of 10 different thogotovirus isolates obtained from various parts of the world for their sensitivity to MxA. A single isolate from Nigeria, Jos virus, showed resistance to the antiviral action of MxA in cell culture and in MxA-transgenic mice, whereas the prototypic Sicilian isolate SiAr126 was fully MxA-sensitive. Further analysis identified two amino acid substitutions (G327R and R328V) in the viral nucleoprotein as determinants for MxA resistance. Importantly, when introduced into SiAr126, the R328V mutation resulted in complete MxA escape of the recombinant virus, without causing any viral fitness loss. The escape mutation abolished viral nucleoprotein recognition by MxA and allowed unhindered viral growth in MxA-expressing cells and in MxA-transgenic mice. These findings demonstrate that thogotoviruses can overcome the species barrier by escaping MxA restriction and reveal that these tick-transmitted viruses may have a greater zoonotic potential than previously suspected.

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Section: Plos Pathogensmentioning

confidence: 99%

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

et al. 2020

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“…Interestingly, avian H7N9 viruses that emerged in 2013 in China (Gao et al 2013) and have since caused severe human infections show reduced MxA sensitivity due to a single amino acid change (N52Y) in NP (Riegger et al 2015). Partial MxA escape might be acquired in pigs which serve as intermediate hosts and possess an antivirally active MX1 protein (Van Dam et al 2019). In fact, the 2009 pandemic H1N1 virus features an MxA escape signature that is suggestive of porcine MX1 evasion (Manz et al 2013).…”

Section: Mxa-mediated Iav Restriction and Escape Are Dictated By A Fementioning

confidence: 99%

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

Haller

Kochs

2019

Hum Genet

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The human MxA protein, encoded by the interferon-inducible MX1 gene, is an intracellular influenza A virus (IAV) restriction factor. It can protect transgenic mice from severe IAV-induced disease, indicating a key role of human MxA for host survival and suggesting that natural variations in MX1 may account for inter-individual differences in disease severity among humans. MxA also provides a robust barrier against zoonotic transmissions of avian and swine IAV strains. Therefore, zoonotic IAV must acquire MxA escape mutations to achieve sustained human-to-human transmission. Here, we discuss recent progress in the field.

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“…Equine Mx1, encoded by a gene located on chromosome 26, is a homolog of MxA from humans or other hosts and has been poorly studied [43,44]. A recent study on the comparison of antiviral activity of Mx1 from different host species includes the corresponding gene from equines and suggests that its antiviral activity against the influenza virus was similar to Mx1 from water buffalo [14]. Here we firstly compared the antiviral potentials of Mx1 proteins from human and equine hosts and identified the potential eqMx1 to inhibit IAV from different species in a species-specific manner.…”

Section: Discussionmentioning

confidence: 99%

“…The MxA protein is an indicator gene that is induced following an interferon action and halts a broad range of viral pathogens including DNA and RNA viruses (mainly Orthomyxoviruses such as influenza [9,10], measles [11], La Crosse [12], and Hantaan viruses [13]). HuMxA is a potent interspecies barrier for influenza viruses from other species [8,10,14].…”

Section: Introductionmentioning

confidence: 99%

“…MxA represents a considerable barrier against the zoonotic introduction of avian influenza viruses into the human population [7]. Interestingly, several investigations reported the antiviral properties of MxA from a human and mouse [10,20,21], porcine [22,23], and bovine [14,[24][25][26] origin. The interspecies transmission would have occurred when avian-origin IAV acquired certain mutations in the NP which overcome the MxA restriction [20,22,27].…”

Section: Introductionmentioning

confidence: 99%

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

Fatima

Zhang

et al. 2019

Viruses

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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.

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Anti-Influenza A Virus Activities of Type I/III Interferons-Induced Mx1 GTPases from Different Mammalian Species

Cited by 9 publications

References 36 publications

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

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

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