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Can a Single Influenza Virus Use Two Different Methods To Infect us?
What if a virus could outmaneuver our defenses by exploiting not just one but two different pathways to invade host cells? Such a possibility might not be science fiction but a stark reality for the influenza A virus (IAV), a persistent culprit behind seasonal flu outbreaks that strain global public health systems year after year.
Beyond its seasonal havoc, IAV looms as a pandemic threat, given its ability to leap from animals—especially birds and pigs—into humans, sparking outbreaks with unpredictable severity. The key to understanding IAV’s infective prowess lies in how it infiltrates host cells. For decades, scientists have focused on a well-established pathway: the virus’s ability to latch onto host cell receptors adorned with sialic acid, a sugar molecule that serves as its molecular “welcome mat.” This interaction has been the cornerstone of our understanding of how IAV begins its infectious cycle. But what if sialic acid isn’t the whole story? What if the virus has a second, hidden pathway that allows it to sneak past cellular defenses and enhance its infective potential? Recent research suggests this might indeed be the case.
In general, the type of sialic acid linkage a virus prefers determines which species it can infect. However, an oddball of the influenza world, the bat IAV strains break this rule. Instead of using sialic acid, they employ a completely different strategy: they hijack major histocompatibility class II (MHC-II) proteins, which are typically involved in immune responses, to sneak into host cells.
Remarkably, bat IAV can use MHC-II receptors from a variety of species, from humans to chickens. What drove this shift in receptor usage, and could other IAV strains do the same? And is it possible for one virus to use both pathways? That is what the researchers from the Institute of Medical Virology in Switzerland tried to find out.
Enter a subtype of IAV (H2N2), which caused a pandemic in 1957 in East Asia. Both human and avian strains of H2N2 have now been shown to have a curious ability: they can not only use the traditional sialic acid receptors but also MHC-II proteins to infect cells. This revelation challenges the previously held belief that only bat IAV can use MHC-II receptors for entry. Interestingly, H2N2 strains can use MHC-II proteins from species like humans, pigs, chickens, ducks, and swans, but not from bats. This finding indicates that the ability to use MHC-II receptors may have been conserved in certain avian strains over time, suggesting a broader host range than previously thought.
What makes this dual receptor usage even more fascinating is that the two entry pathways— sialic acid and MHC-II—seem to function independently of one another. The researchers identified the specific amino acids that enable the H2N2 virus to interact with MHC-II, but more work is needed to pinpoint where this exactly happens. While this MHC-II-mediated entry boosts infection in airway epithelial cells and immune cells like macrophages, it also raises questions about how this impacts the virus’s overall ability to spread and cause disease.
Not all IAV strains share this trait, however. Other IAV subtypes, such as H1, H5, and H6, do not seem to possess the ability to use MHC-II for entry, even though they are phylogenetically related to H2. This raises intriguing questions about why the H2 subtype evolved to acquire this additional capability while its relatives did not. Could it be that H2 IAV strains, particularly those from Eurasian avian lineages, have a unique evolutionary advantage due to their dual receptor usage? Or perhaps they were exposed to different selective pressures favoring this alternative entry mechanism.
This discovery gives us a fresh perspective on how influenza viruses might have evolved to target specific receptors. Scientists had speculated about an early version of the virus that could use both sialic acid and MHC-II receptors, but there wasn’t solid proof until now. The fact that modern avian H2N2 strains still have this capability suggests that the dual receptor system may have been a critical factor in the virus’s ability to adapt to multiple hosts, including humans. As more unconventional IAV strains, such as the recently discovered H19 subtype, continue to emerge with unique receptor preferences, we may need to rethink what we know about how these viruses work and spread.
The implications for public health are significant. If H2N2 viruses can infect a wide range of species via multiple entry routes, the potential for these viruses to spark a new pandemic should not be ignored. Indeed, previous studies have demonstrated that avian H2N2 strains, especially those from Eurasia, are capable of replicating efficiently and causing disease in mammalian models. With this new understanding of the virus’s ability to use MHC-II proteins for entry, it is clear that increased surveillance of avian H2 IAV is needed as part of pandemic preparedness efforts.
The key question, then, is whether this dual receptor usage makes the virus more likely to jump species barriers and cause future outbreaks in humans. As researchers continue to unravel the mysteries of how IAV interacts with host receptors, one must ask: what other hidden tricks do these viruses have up their sleeves, and how prepared are we to face them?
Link to the original post: Karakus, U., Sempere Borau, M., Martínez-Barragán, P., von Kempis, J., Yildiz, S., Arroyo-Fernández, L. M., Pohl, M. O., Steiger, J. A., Glas, I., Hunziker, A., García-Sastre, A., & Stertz, S. (2024). MHC class II proteins mediate sialic acid independent entry of human and avian H2N2 influenza A viruses. Nature microbiology, 9(10), 2626–2641. https://doi.org/10.1038/s41564-024-01771-1
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