H18 haemagglutinin binds MHC class II at a site distant from the canonical sialic-acid binding site
This study reveals that the bat-derived influenza H18 haemagglutinin binds to MHC class II molecules at a novel site distinct from the canonical sialic-acid pocket, inducing conformational changes that prime viral fusion and demonstrating the protein's structural adaptability to utilize protein receptors for host entry.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Viruses are masters of disguise and adaptation, but they share a fundamental weakness: they cannot enter a cell on their own. To breach the cellular fortress, they must first find a specific door handle, a receptor on the cell's surface that matches a key on the virus's outer shell. For most influenza viruses, this key is a sugar molecule called sialic acid, which sits atop long chains of sugars coating the surface of cells in birds and humans. The virus's key, a protein called hemagglutinin, is shaped to grab these sugars, allowing the virus to hitch a ride inside. This lock-and-key mechanism is so consistent that scientists have long believed it was the only way influenza could enter a cell. However, a strange group of influenza viruses found only in bats broke this rule. Instead of using sugar keys, these bat viruses use a completely different type of door handle: a protein called MHC class II, which is part of the immune system's communication network. For years, scientists knew these bat viruses used this protein, but they did not know how the viral key fit into the protein lock, or how the virus managed to open the door without its usual sugar-detecting tools.
A team of researchers has now mapped this interaction in high detail, revealing how the bat influenza virus H18N11 hijacks the human immune protein to enter cells. By combining advanced imaging techniques with chemical analysis, the scientists discovered that the virus uses a completely different part of its surface to grab the protein receptor. In the standard influenza virus, the binding site is a deep pocket designed to hold a sugar molecule. In the bat virus, this pocket is empty and useless for sugars. Instead, the virus uses a flat, exposed patch on the side of its head to bind directly to the immune protein. This patch is located about 30 angstroms away from where a sugar-binding pocket would normally be, a distance that shows the virus has evolved a completely new way to hold on. The researchers measured the strength of this new grip and found it to be surprisingly strong, binding with a strength in the range of micromolar concentrations, which is significantly tighter than the weak, fleeting interactions typical of sugar binding. This strong, direct hold is likely necessary because the immune proteins the virus targets are far less common on the cell surface than the abundant sugar chains used by other flu viruses.
The study also uncovered a clever trick the virus uses to ensure it can get inside the cell once it has latched on. In many viruses, simply grabbing the receptor is enough to trigger the next step: the fusion of the viral shell with the cell membrane. The researchers found that when the bat virus grabs the immune protein, it sends a signal through its own structure that starts to loosen the virus's internal machinery. This "priming" effect makes the virus more ready to fuse with the cell, a process that usually requires a drop in acidity to trigger. The data suggests that the act of binding to the immune protein itself helps prepare the virus for entry, a mechanism that is distinct from how standard flu viruses operate. To confirm that this specific binding site was essential, the scientists made small changes to the virus's surface, swapping out key amino acids for others that would not fit the lock. These changes prevented the virus from fusing with cells and stopped it from growing in the lab, proving that this specific interaction is not just a side effect but the critical step for infection.
Perhaps the most striking finding was how the virus can repair itself if this binding site is damaged. When the researchers introduced a mutation that weakened the virus's ability to bind, the virus did not simply die out. Instead, it evolved a second change that removed a small sugar coating from its own surface. This sugar, which normally sits near the binding site, was actually blocking the virus's view of the receptor. By shedding this sugar, the virus cleared the path and restored its ability to bind tightly to the immune protein, regaining its ability to infect cells. This discovery highlights a remarkable flexibility in how viruses adapt; they can modify their own surface decorations to improve their grip on a receptor, even if that receptor is a protein rather than a sugar. These findings provide a clear picture of how a virus can switch from using sugar keys to protein keys, a shift that required a complete retooling of its entry mechanism. As scientists continue to monitor these bat viruses, understanding exactly how they bind to immune proteins will be crucial for predicting if they might jump to other species, including humans, and how they might evolve to overcome our defenses.
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