First discovery: Rare MX1 mutation increases human susceptibility to H7N9 virus

The avian influenza virus H7N9 is a zoonotic avian influenza virus (IAV).
It rarely spreads to humans, but once it occurs, the mortality rate exceeds 30%, far exceeding the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)
.

Occupational poultry breeders are at high risk of H7N9 infection, but only account for 7% of all cases, and the continuous transmission of H7N9 between humans has not been observed, indicating that host genes play an important role in virus susceptibility

The Shu Yuelong team of the School of Public Health of Sun Yat-sen University conducted a study on this.
Using a case-control study method, a total of 217 confirmed cases of H7N9 avian influenza and 116 occupational exposure controls with epidemiological associations with the confirmed cases were included.
Whole-genome sequencing Based on genetic association analysis, it was discovered for the first time that rare mutations in the human MX1 gene may increase the risk of human infection with the H7N9 avian influenza virus
.

This major breakthrough was recently published in the Science journal

DOI: 10.
1126/science.
abg5953

Myxovirus resistant (Mx) is one of the first interferon-induced antiviral genes discovered.
The human MX1 gene can encode human myxovirus resistance protein A (Human myxovirus resistance protein A, MxA), which is a dynamic protein.
GTPase, a class of macromolecules in the superfamily, has antiviral effects on a variety of RNA viruses and DNA viruses, including influenza A viruses and hepatitis B viruses
.

The research team found a total of 17 rare variants of MX1 in H7N9 avian flu cases
.

In vitro infection experiments and influenza polymerase activity testing showed that 14 of these mutations will affect protein function, and these 14 mutant MxA proteins not only lose their inhibitory effect on H7N9 avian influenza viruses, but also lose their inhibitory effects on H7N7 and H5N1 avian influenza viruses.

Mutations in H7N9 patients cause MxA to lose antiviral activity

The sequencing results of 217 confirmed cases of H7N9 avian influenza showed that the rare mutations of MX1 carried by H7N9 cases were all heterozygous mutations, and the antiviral activity of MxA required oligomerization
.

Therefore, the author speculates that the inactivated MxA variants may play a dominant and negative effect on the co-expressed WT MxA

Co-immunoprecipitation analysis confirmed that all inactive MxA missense variants physically interacted with WT MxA
.

The mutation p.

The formation of antiviral inactive MxA hetero-oligomers leads to dominant negative effects

This study found for the first time that rare mutations in the MX1 gene can increase the risk of human infection with the avian influenza virus
.

This result explains the epidemiological phenomenon that only a few people will be infected with the H7N9 avian influenza virus under the same exposure conditions

This study provides genetic evidence for the key role of MX1-based antiviral defenses in the control of IAV animal infections
.

At the same time, it also provides a scientific basis for the monitoring of high-risk populations, and further promotes the precise prevention and control of infectious diseases

Reference materials:

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