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How does the influenza virus hack our cells?

Flu epidemics are caused by influenza A or B viruses, resulting in acute respiratory infections and killing about half a million people worldwide each year, while also affecting a variety of other animals, as in the case of the avian flu. Moreover, these viruses’ high capacity for mutation makes them particularly elusive and hard to combat. 

Now, a team of researchers led by the University of Geneva (UNIGE) has discovered that the influenza A virus manages to penetrate and infect cells by attaching itself to a receptor on the cell surface and hijacking the organism’s iron transport mechanism to start its infection cycle. Since, by blocking this particular receptor, the experts managed to significantly reduce the virus’ ability to invade cells, this finding could potentially be exploited to combat flu infections and mitigate epidemics.

What the researchers learned 

“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. However, we did not know which proteins on the host cell surface marked this entry point, and how they favored the entry of the virus,” explained study senior author Mirco Schmolke, an associate professor of Microbiology and Molecular Medicine at UNIGE.

At first, the researchers identified cell surface proteins from the vicinity of the viral haemagglutinin, the protein the influenza A virus uses to enter the cells. One of these proteins – called “transferrin receptor 1” – which helps transporting iron molecules that are essential for many physiological functions into the cell was found to play a major role in how the virus succeeds in penetrating the cells.

“The influenza virus takes advantage of the continuous recycling of the transferrin receptor 1 to enter the cell and infect it,” said lead author Béryl Mazel-Sanchez, a senior scientist at the biopharmaceutical company CSL Behring and a former post-doctoral researcher in Schmolke’s lab. 

“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.”

Promising results

In a follow-up experiment, the scientists managed to use a chemical molecule to reproduce this mechanism by inhibiting the transferrin receptor 1. “We tested it successfully 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. However, in view of its potentially oncogenic characteristics, this product cannot be used to treat humans,” Mazel-Sanchez explained. 

Nonetheless, anti-cancer therapies based on the inhibition of the transferrin receptor could potentially benefit from these discoveries.

In addition to this particular receptor, the researchers have also identified about 30 other proteins that may play a role in how the influenza A virus enter the cells. Although it is likely that the virus uses a combination involving other receptors to infect cells, further research is needed to clarify these mechanisms.

“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 authors concluded.

The study is published in the journal Proceedings of the National Academy of Sciences.

More about the influenza virus 

Influenza is a highly contagious viral infection that primarily spreads through the upper and/or lower respiratory tract. It is more commonly known as the flu. The influenza viruses are members of the Orthomyxoviridae family and are categorized into four types: A, B, C, and D.

Flu types

Influenza A viruses are the most virulent human pathogens among the four influenza types and cause the most severe disease. The influenza A virus can be broken down into different subtypes based on the chemical structure of hemagglutinin (H) and neuraminidase (N) proteins on their surface. For instance, H1N1 and H3N2 are subtypes of influenza viruses that have caused human pandemics.

Influenza B viruses are not divided into subtypes, but can be broken down into lineages and strains. Currently circulating influenza B viruses belong to one of two lineages: B/Yamagata and B/Victoria. Influenza B is less common but can still cause outbreaks of seasonal flu.

Influenza C viruses cause only mild respiratory illness, or no symptoms at all, so they do not cause epidemics or pandemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people.

Flu viruses can change through a process called antigenic drift and shift. Antigenic drift happens gradually over time as the virus makes small changes to its genetic composition, while antigenic shift is an abrupt, major change to the influenza A viruses, resulting in new hemagglutinin and/or new neuraminidase proteins.

Symptoms of infection 

Influenza is characterized by sudden onset of high fever, aching muscles, headache, severe malaise, non-productive cough, sore throat, and rhinitis. Most people recover from fever and other symptoms within a week without requiring medical attention. But influenza can cause severe illness or death in high-risk populations such as the very young, elderly, and individuals with certain chronic health conditions.

Flu vaccination

Vaccination is the most effective way to prevent infection and severe outcomes caused by influenza viruses. Antiviral drugs are also available and can make your illness milder and make you feel better faster. They can also prevent serious flu complications.

Despite the availability of vaccines, the flu virus remains a major public health concern, largely due to its ability to change and mutate over time. Scientists are actively researching ways to develop a universal flu vaccine that would protect against all strains of the virus.


By Andrei Ionescu, Staff Writer

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