Rare gene variant increases zoonotic H7N9 virus susceptibility in humans

Rare, single-nucleotide variants in the MX1 gene increase human susceptibility to zoonotic H7N9 avian influenza infection, according to a new study.

The findings, which provide genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic influenza A virus (IAV) infections in humans, suggest that individuals with such genetic vulnerabilities could act as incubators for transmission of virulent new IAV subtypes. Although zoonotic avian influenza infections are rare, spillover events remain a concern as they can represent a source of new pandemic virus strains.

One of the most recent outbreaks was caused by the H7N9 avian influenza virus, first identified in humans in 2013. While human infections of H7N9 remain relatively uncommon and sustained transmission of the virus between humans has not yet been observed, this influenza subtype can be particularly deadly, having a mortality rate of roughly 39%, far exceeding that of SARS-CoV-2. Despite their potential risks, the molecular mechanisms that enable cross-species transmissions of IAVs are not well understood.

Currently, exposure to poultry is the main risk factor for human H7N9 infection. However, occupational poultry workers represent only 7% of all reported cases. These observations suggest that human genetic factors may play a role in zoonotic virus susceptibility. Yongkun Chen and colleagues used whole-genome sequencing to investigate the role of rare gene mutations in H7N9 infection in 220 Han Chinese patients confirmed to have had H7N9 infection between 2013 and 2017 and among a population of healthy poultry workers who can be highly exposed to the virus, as controls.

In workers with lab-confirmed H7N9 infections, Chen et al. discovered multiple defective single-nucleotide variants in the MX1 gene, which codes for an interferon-induced antiviral protein known to control IAV infections in mice. According to the authors, the majority of the identified MX1 variants (14 out of 17) had lost the ability to inhibit avian IAV, including H7N9, in in vitro infection experiments in human cells. "In the future," say the authors, "to decrease the risk of pandemic viruses, it will be important for disease surveillance…to screen vulnerable human populations for deleterious variations in MX1."