A groundbreaking discovery has unveiled a new pathway by which certain flu viruses can enter human cells, potentially increasing their ability to spread between species and posing a serious threat of future pandemics. While most flu viruses typically enter cells by binding to sugar molecules called sialic acids on the cell surface, a study published in the journal *Nature Microbiology* has identified a ‘back door’ entryway used by some viruses. This alternate route involves the major histocompatibility complex class II (MHC-II) pathway, which had previously been speculated but never confirmed. The research team examined various flu virus subtypes, including H1N1, H3N1, and H2N2, known to have caused epidemics in the past. They discovered that the H2N2 subtype exhibited a remarkable ability to utilize both the traditional sialic acid route and the newly identified MHC-II pathway. Notably, H2N2 viruses were found to enter cells with high MHC-II expression levels ten times more efficiently than those lacking the MHC-II pathway, even though both cell types had equal sialic acid levels on their surfaces. Further investigation using gene editing techniques confirmed that MHC-II complexes are indeed an entry route for these viruses. The study also identified specific amino acids within the viral structure that are crucial for binding to the MHC-II ‘back door’ receptor. Interestingly, these viruses were shown to replicate faster and reach higher concentrations in human lung cells compared to those solely relying on the ‘front door’ entry. This increased replication potential could translate to a heightened risk of causing disease and spreading between humans. The study also highlights a crucial concern – this ‘back door’ entryway is not limited to human flu viruses. Avian H2N2, a bird flu virus responsible for a pandemic in the 1950s, can also utilize this pathway. While currently residing in avian reservoirs, these H2 viruses can infect a range of animals including pigs, mice, ferrets, and birds, raising concerns about potential zoonotic transmission. The ability of H2 viruses to exchange genes with other flu viruses further increases the likelihood of a zoonotic event. This discovery prompts a renewed focus on pandemic preparedness, particularly concerning viruses that can utilize multiple entry routes. Scientists emphasize the need to understand the relevance of this MHC-II pathway in interspecies transmission and to assess its potential contribution to the emergence of ‘super viruses’ circulating in animal populations. This knowledge is crucial for accurately identifying high-risk scenarios and implementing effective measures to prevent future flu pandemics.
