A whole genome sequencing (WGS) study has been the first to demonstrate a strong association between infection with the avian influenza A virus (IAV) H7N9 and rare, heterozygous single-nucleotide variants (SNVs) in the MX1 gene encoding for the myxovirus resistance protein A (MxA).

"MxA is an interferon- (IFN)-regulated antiviral protein factor with activity against a variety of RNA and DNA viruses, including influenza viruses," said Yuelong Shu, a professor and dean of the School of Public Health at Sun Yat-sen University in Guangzhou.

"The new WGS study comparing IAV H7N9-infected patients with healthy poultry worker controls is the first to demonstrate a strong association between H7N9 infection and rare heterozygous SNVs in the MX1 gene," Shu told BioWorld Science.

These findings strongly suggest that future disease surveillance programs in humans should monitor MxA sensitivity of new avian influenza viruses and screen vulnerable populations for MX1 variations, the authors reported in the August 20, 2021, issue of Science.

Besides providing genetic evidence for a key role of the MX1-based antiviral defense in controlling zoonotic avian flu infections in humans, the study's findings indicate that patients with such genetic vulnerabilities may be incubators for the transmission of virulent new avian flu subtypes.

Although zoonotic avian flu infections are uncommon, crossover events do occur and represent a potential source of new pandemic virus strains such as the H7N9 avian influenza virus first identified in humans in China in 2013.

While H7N9 human infections are also relatively rare, and sustained human-human viral transmission has not yet been seen, this strain is associated with a mortality rate of approximately 39%, far exceeding that of the current SARS-CoV-2 pandemic.

However, despite these potential risks, the molecular mechanisms underlying cross-species transmissions of avian influenza viruses remain poorly understood.

Human exposure to infected poultry is the main risk factor for human H7N9 infection. Still, just 7% of all reported cases occur in poultry workers, suggesting the importance of human genetic factors in zoonotic virus susceptibility.

In the new Science study, the authors investigated the role of rare gene mutations in H7N9 infections in 220 Chinese patients, compared with 121 epidemiologically linked healthy poultry worker controls using WGS.

In those with laboratory-confirmed H7N9 infections, multiple single-nucleotide variants were discovered in the MX1 gene, which encodes for the MxA IFN-induced antiviral protein known to control IAV infections in transgenic mice.

In addition, the majority of the MxA variants identified had lost the ability to inhibit avian flu viruses, including H7N9, in transfected human cell lines.

"These results suggest that the MxA variants have lost their antiviral activity and may even confer susceptibility to the influenza virus," Shu said.

Moreover, nearly all of the inactive MxA variants exerted a dominant-negative effect on the antiviral function of wild-type (WT) MxA, suggesting an MxA null phenotype in heterozygous carriers.

"Based on our cell culture experiments, the inactive MxA variants were demonstrated to completely abrogate the activity of the WT MxA," said study co-leader Martin Schwemmle, a professor in the Institute of Virology at the University of Freiburg in Germany.

"Avian influenza viruses in particular are highly sensitive to the antiviral activity of MxA, as they lack MxA escape mutations in the viral nucleoprotein that are otherwise present in human circulating influenza viruses."

Therefore, "we assume that the heterozygous carriers are not protected against these viruses," Schwemmle told BioWorld Science.

Together, these results provide genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic IAV infections in humans.

In future, in order to decrease the risk of pandemic viruses in human populations, it will therefore be important for disease surveillance to screen vulnerable human populations for deleterious variations in MX1.

"Our study indicates that patients harboring variants are susceptible to zoonotic influenza infection, which will provide greater opportunities for such viruses to become adaptive to humans, causing potential human-to-human transmission, hence the need for surveillance," said Shu.

"Avian influenza viruses are not fit enough to replicate in human tissue and thus need time to adapt to the cellular environment," noted Schwemmle.

"In patients with deleterious MX1 SNVs, there is more time for adaptation, which might allow emergence of new variants transmissible to other persons," he cautioned.

"Our study findings are consistent with those of others showing that host genetic factors play important roles in emerging infectious diseases including influenza and coronaviruses," noted Shu.

Therefore, in future "we will continue searching for further factors and mechanisms in order to provide both evidence and clues for antiviral drug discovery."

"Our study demonstrated the feasibility of identifying critical host factors that prevent zoonotic viral infections and should encourage other groups to do similar work with other virus in a defined patient cohort," said Schwemmle.

"MxA possesses a broad antiviral activity, so may also be of critical importance in controlling viral infections other than influenza."