How the flu virus enters our cells

Influenza epidemics, caused by influenza A or B viruses, result in acute respiratory infection and kill half a million people worldwide every year as well as wreaking havoc on animals. A team from the University of Geneva (UNIGE) has now identified how the influenza A virus manages to penetrate cells to infect them: by attaching itself to a receptor on the cell surface, it hijacks the iron transport mechanism to start its infection cycle. Their work has been published in the journal PNAS.

“We already knew that the influenza A virus binds to sugar structures on the cell surface, then rolls along the cell surface until it finds a suitable entry point into the host cell,” said UNIGE Associate Professor Mirco Schmolke. “However, we did not know which proteins on the host cell surface marked this entry point, and how they favoured the entry of the virus.”

The scientists first identified cell surface proteins present in the vicinity of the viral haemagglutinin, the protein used by the influenza A virus to enter the cell. One of these proteins stood out: transferrin receptor 1. This acts as a revolving door transporting iron molecules into the cell, which are essential for many physiological functions.

“The influenza virus takes advantage of the continuous recycling of the transferrin receptor 1 to enter the cell and infect it,” said Béryl Mazel-Sanchez, a former postdoctoral researcher in Schmolke’s laboratory and first author of the study. “To confirm our discovery, we genetically engineered human lung cells to remove the transferrin receptor 1, or on the contrary to overexpress it. By deleting it in cells normally susceptible to infection, we prevented influenza A from entering. Conversely, by overexpressing it in cells normally resistant to infection, we made them easier to infect.”

The research team succeeded in reproducing this mechanism by inhibiting the transferrin receptor 1 using a chemical molecule. According to Mazel-Sanchez, the inhibitor was subsequently tested on human lung cells, on human lung tissue samples and on mice with several viral strains.

“In the presence of this inhibitor, the virus replicated much less,” she said. “However, in view of its potentially oncogenic characteristics, this product cannot be used to treat humans.” That said, anticancer therapies based on the inhibition of the transferrin receptor are currently under development.

In addition to the transferrin receptor 1, scientists have identified some 30 other proteins whose role in the influenza A entry process remains to be deciphered. It is indeed likely that the virus uses a combination involving other receptors.

“Although we are still far from a clinical application, blocking the transferrin receptor 1 could become a promising strategy for treating influenza virus infections in humans and potentially in animals,” the study authors said.

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