Flu outbreaks, caused by flu A or B viruses, lead to sudden lung infection. They claim 500,000 lives globally each year. These viruses can also cause chaos in animals, such as the case of bird flu. Researchers from UNIGE uncovered how flu A virus enters cells for infection. By binding to a cell surface receptor, it seizes the iron transport system to initiate infection. Blocking the receptor diminished its cell invasion. Published in PNAS, these findings reveal an exploitable weakness for combating the virus.

Influenza viruses pose significant risks to both human and animal health. Their ability to mutate makes them particularly elusive. "We were already aware that the influenza A virus binds to sugar structures on the cell surface, then moves along the surface until it identifies a suitable entry point into the host cell. However, the specific proteins on the host cell surface that serve as entry points and how they facilitate virus entry were previously unknown," explains Mirco Schmolke, an associate professor in the Department of Microbiology and Molecular Medicine and the Geneva Centre for Inflammation Research (GCIR) at the UNIGE Faculty of Medicine, who led this research.

The researchers initially identified cell surface proteins located near the viral haemagglutinin, the protein utilized by the influenza A virus for cell entry. Among these proteins, one stood out: transferrin receptor 1. This receptor functions as a rotating gateway for transporting iron molecules into the cell, which play a crucial role in various physiological functions.

"The influenza virus exploits the continuous recycling mechanism of transferrin receptor 1 to enter and infect the cell," explains Béryl Mazel-Sanchez, a former post-doctoral researcher in Schmolke's laboratory and the lead author of this study. "To validate our discovery, we genetically modified human lung cells by either removing or overexpressing the transferrin receptor 1. When we deleted the receptor in normally susceptible cells, we prevented the entry of influenza A virus. Conversely, when we overexpressed the receptor in normally resistant cells, we made them more susceptible to infection."

The research team then achieved the replication of this mechanism by inhibiting the transferrin receptor 1 using a chemical compound. "We successfully tested this inhibitor on human lung cells, samples of human lung tissue, and mice infected with various viral strains," says Mazel-Sanchez. "In the presence of this inhibitor, the virus exhibited significantly reduced replication. However, due to its potential oncogenic properties, this particular compound cannot be used for human treatment." On the other hand, there are ongoing developments of anti-cancer therapies that involve the inhibition of the transferrin receptor, which could also be of interest in the context of combating influenza.

"The success of our discovery was made possible through the outstanding collaboration within the Faculty of Medicine, as well as with the University Hospitals of Geneva (HUG) and the Swiss Institute of Bioinformatics (SIB)," the authors emphasize. Alongside the identification of transferrin receptor 1, researchers have also identified around 30 other proteins whose role in the entry process of influenza A virus remains to be deciphered. It is likely that the virus employs a combination involving these other receptors. "While we still have a long way to go before clinical application, the blockade of transferrin receptor 1 could become a promising strategy for treating influenza virus infections in humans and potentially in animals."

Source: Université de Genève (University of Geneva)