Most influenza viruses enter human or animal cells through specific pathways on the cell surface. Researchers from the University of Zurich have now discovered that certain human flu viruses and bird flu viruses can also use a second route of entry, an immune system protein complex, to infect cells. This ability helps the viruses infect different species – and possibly jump between animals and humans.
Most type A influenza viruses circulating in birds and pigs do not normally pose a health risk to humans. However, the viruses could pose a threat if an outbreak like the one currently occurring in U.S. dairy cattle occurs or during seasonal epidemics. In rare cases, a virus can jump from animals to humans – with potentially devastating consequences such as a global pandemic.
Additional receptor provides alternative access route
Most influenza viruses enter host cells using their envelope proteins, which rise from the surface as spikes. The so-called hemagglutinin binds to sialic acid, a chemical group on the surface of human cells and the cells of various animal species. An international research team led by Professor Silke Stertz from the Institute of Medical Virology at the University of Zurich (UZH) has now shown that influenza viruses also have a second method of infecting host cells. “Human influenza A viruses of the H2N2 subtype and related H2N2 avian influenza viruses can enter cells through a second receptor. They use an alternative route of entry,” says Stertz.
The researchers discovered that hemagglutinin also binds to MHC class II protein complexes. These complexes on the surface of certain immune and respiratory cells are responsible for distinguishing 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.
Transmission from animals to humans likely
This dual ability to infect cells was observed in laboratory-grown cell lines and human airway cultures. How well the viral receptor fits onto cell surface structures plays a crucial role in determining which host species and tissues are infected and ultimately how severe the infection will be. Receptor specificity also influences whether a virus can infect different animal species or even humans (zoonosis). “Our finding shows that influenza viruses can adapt to use different entry routes. This could affect their ability to infect different species and possibly jump between animals and humans,” the UZH virologist emphasizes.
The risk that avian, swine and other animal influenza viruses could cause an influenza pandemic in humans may therefore be greater than previously thought. The ability to use MHC class II proteins for cell entry may have been one of the reasons why H2N2 influenza viruses emerged as a pandemic virus in Asia in 1957. This is another good reason to increase global influenza surveillance in both animals and humans.
