IFITM3 variants point to a critical role in emergent virus infections.

Interferon-induced transmembrane protein 3 (IFITM3) is a cellular protein that restricts numerous viral infections by blocking virus-host membrane fusion. In humans, there are two IFITM3 single nucleotide polymorphisms (SNPs), rs12252-C and rs34481144-A, that decrease IFITM3 activity and have been associated with severe illness following influenza virus infections. Mice lacking IFITM3 show increased influenza severity, supporting this association. However, some studies do not find a consistent link between IFITM3 SNPs and infection severity, causing uncertainty about its role in vivo. Review of the literature indicates that IFITM3 SNPs are primarily associated with increased viral disease in infections with emergent influenza viruses, such as the 2009 H1N1 pandemic virus and zoonotic H7N9 virus. Similarly, IFITM3 SNPs are reported to be risk factors for increased severity in other emergent infections, including SARS-CoV-2, Hantaan virus, and HIV. In contrast, most studies that failed to find an association examined seasonal influenza. We posit that adaptive immune mechanisms, including pre-existing antibodies and memory T cells against seasonally circulating viruses, compensate for IFITM3 deficiencies, therefore masking its role in seasonal influenza. We propose that IFITM3 is most critical in defending against emergent viruses and should be a key focus of public health strategies to prevent the emergence and spread of novel pathogens, with individuals carrying IFITM3 SNPs potentially benefiting from broadened vaccine coverage, avoidance of animal reservoirs, or enhanced masking to protect themselves and the wider population.