Rare variant
            <i>MX1</i>
            alleles increase human susceptibility to zoonotic H7N9 influenza virus

Chen, Yongkun; Graf, Laura; Chen, Tao; Liao, Qijun; Bai, Tian; Petric, Philipp P.; Zhu, Wenfei; Yang, Lei; Dong, Jie; Lü, Jian; Chen, Ying; Shen, Juan; Haller, Otto; Staeheli, Peter; Kochs, Georg; Wang, Dayang; Schwemmle, Martin; Shu, Yuelong

doi:10.1126/science.abg5953

Cited by 57 publications

(61 citation statements)

References 53 publications

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“…For example, the unusually high number of human infections caused by H7N9, has been correlated with changes in the viral glycoproteins, and the polymerase complex 21 . Correlation between disease severity induced by H7N9 and certain human Mx1 alleles has also been described in GWAS studies 22 .…”

Section: Main Textmentioning

confidence: 71%

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Pinto

Bakshi

Lytras

et al. 2022

Preprint

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Cross-species transmission of avian influenza A viruses (IAVs) into humans could represent the first step of a future pandemic1. Multiple factors limiting the spillover and adaptation of avian IAVs in humans have been identified, but they are not sufficient to explain which virus lineages are more likely to cross the species barrier1,2. Here, we identified human BTN3A33 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human IAVs. We determined that BTN3A3 is constitutively expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts at the early stages of virus replication by inhibiting avian IAV vRNA transcription. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F, or rarely 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, several serotypes of avian IAVs that spilled over into humans in recent decades evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure4. Importantly, we identified more than 150 avian IAV lineages with a BTN3A3-resistant genotype. In conclusion, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

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Section: Main Textmentioning

confidence: 71%

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Pinto

Bakshi

Lytras

et al. 2022

Preprint

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“…The gene MX1 mentioned above has a similar antiviral effect. A guanosine triphosphate (GTP) metabolic protein is encoded by MX1 and has an interferon-induced antagonistic effect on the RNA or DNA replication process of viruses [30] . Other genes (IFIT1, IFIT2, IFIT3, IFI6, RSAD2, OAS2 and OAS3 [31] ) encode similar interferon-inducible proteins that have antiviral effects.…”

Section: Discussionmentioning

confidence: 99%

Analysis of differentially expressed genes between paroxysmal and persistent atrial fibrillation

Ning

Wang

et al. 2022

Preprint

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Background This study aims to analyze the differentially expressed long noncoding RNAs and messenger RNAs (DELncRNAs and DEmRNAs) in patients with paroxysmal and persistent atrial fibrillation and explore the novel AF-related molecular mechanisms.Methods Two target datasets about paroxysmal and persistent atrial fibrillation patients (GSE75092 and GSE113013) were downloaded and further analyzed from the Gene Expression Omnibus database by R software. Upregulated and downregulated differentially expressed genes (DEGs) and the co-expressed differentially expressed genes (co-DEGs) of the two datasets were identified, of which enrichment analyses and protein-protein interaction network construction were performed. Results A total of 127 DELncRNAs and 321 DEmRNAs were screened in GSE75092; a total of 46 DELncRNAs and 64 DEmRNAs were screened in GSE113013. 8 co-DEGs were further identified in the overlap between the two datasets on Venn Diagram, which comprises 3 LncRNA and 5 mRNA. GO and KEGG analysis were successfully performed on the DEGs and co-DEGs mentioned above and the protein-protein interaction network of DEGs was constructed.Conclusions Multiple DEGs were found in patients with either paroxysmal or persistent atrial fibrillation and their functions were mainly enriched in metabolism and inflammation-related signaling pathways. The antiviral defense mechanism of PAF is an interesting difference we found.

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“…The discovery of such cofactor(s), if they exist, would probably be a major turning point to understand the mechanism of action of MX1 proteins. Allelic variation studies have been performed for HsMX1 (60,61), with only one variant being discovered in the N-terminal domain where a premature stop codon was found at amino acid position 30 (Q30*) causing a truncated, antivirally inactive protein (61). Using the gnomAD browser (https://gnomad.broadinstitute.org), a single variant can be found in a single individual implicating L41 of HsMX1 where a missense deletion of 1 base occurred (21-42807777-AC-A) inducing a frameshift.…”

Section: Discussionmentioning

confidence: 99%

The N-terminal domain of MX1 proteins is essential for their antiviral activity against different families of RNA viruses

McKellar

Arnaud-Arnould

Chaloin

et al. 2022

Preprint

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Myxovirus resistance protein 1 (MX1) and MX2, are homologous, dynamin-like large GTPases, induced upon interferon (IFN) exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus (IAV), by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood. MX1 proteins are mechano-enzymes and share a similar organization to dynamin, with an amino-terminal GTPase domain and a carboxy-terminal stalk domain, connected by a Bundle Signalling Element (BSE). These three elements are known to be essential for antiviral activity. HsMX1 has two unstructured regions, the L4 loop, also essential for antiviral activity, and a short amino (N)-terminal region, which greatly varies between MX1 proteins of different species. The role of this N-terminal domain in antiviral activity is not known. Herein, using mutagenesis, imaging and biochemical approaches, we demonstrate that the N-terminal domain of HsMX1 is essential for antiviral activity against IAV and Vesicular Stomatitis Virus (VSV), and for the ability to aggregate Orthobunyavirus nucleoproteins. Furthermore, we pinpoint a highly conserved leucine within this region, which is absolutely crucial for human, mouse and bat MX1 protein antiviral activity. Importantly, mutation of this leucine does not compromise GTPase activity or oligomerization capabilities, but does modify MX1 protein subcellular localisation. The discovery of this essential and highly conserved residue defines this region as key and may reveal insights as to the mechanism of action of MX1 proteins.

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Rare variant MX1 alleles increase human susceptibility to zoonotic H7N9 influenza virus

Cited by 57 publications

References 53 publications

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Analysis of differentially expressed genes between paroxysmal and persistent atrial fibrillation

The N-terminal domain of MX1 proteins is essential for their antiviral activity against different families of RNA viruses

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