Flu Virus Uses Second Pathway to Infect Cells

The majority of influenza viruses enter animal or human cells through particular surface-based routes. It has recently been found by researchers at the University of Zurich that some influenza viruses, both human and avian, can also enter cells through a second entry point that involves an immune system protein complex. This feature aids in the viruses’ ability to spread to other species and possibly even between humans and animals.

Most type A influenza viruses that are currently plaguing pigs and birds don’t often pose a threat to human health. Nevertheless, the viruses might be dangerous during seasonal epidemics or in the event of an outbreak similar to the one that is affecting dairy cattle in the US at the moment. Rarely, a virus can spread from animals to people, which could have disastrous effects like a worldwide pandemic.

An extra receptor provides a different entrance route
The majority of influenza viruses employ their envelope proteins, which protrude from the surface like spikes, to enter host cells. The chemical group sialic acid, which is present on the surface of both human and animal cells, is bound by the so-called hemagglutinin. It has now been demonstrated by an international research team headed by Professor Silke Stertz of the University of Zurich’s (UZH) Institute of Medical Virology that flu viruses also possess a second way of infecting host cells.

“Human influenza A viruses of subtype H2N2 and related H2N2 avian influenza viruses can enter cells through a second receptor. They use an alternative entry pathway.” – Professor Silke Stertz, Institute of Medical Virology, University of Zurich

The researchers found that hemagglutinin also binds to MHC class II protein complexes. These complexes on the surface of certain immune and respiratory cells are responsible for differentiating between the body’s own cells and foreign cells. “We found that MHC class II complexes in humans, pigs, ducks, swans and chickens allow viruses to enter cells, but not those in bats,” says Stertz.

Possibility of animal-to-human transmission
Both human airway cultures and lab-grown cell lines showed this dual capacity for infection. The degree of infection and the host species and tissues that are infected are largely determined by how well the viral receptor attaches to the cell surface structures. Receptor specificity also affects a virus’s ability to infect humans or other animal species (zoonosis). “Our research demonstrates that influenza viruses are adaptable enough to utilize many entry points. According to the UZH virologist, “this might influence their ability to infect different species and potentially jump between animals and humans.”

Thus, there may be a higher chance than previously thought that swine, avian, and other animal influenza viruses might start a global flu pandemic in humans. One of the possible causes of the 1957 H2N2 influenza pandemic in Asia could have been the virus’s capacity to utilize MHC class II proteins for cell entry. This just serves as another justification for increasing worldwide influenza surveillance for both humans and animals.

For more information: MHC class II proteins mediate sialic acid independent entry of human and avian H2N2 influenza A viruses, Nature Microbiology,  https://doi.org/10.1038/s41564-024-01771-1