The Influenza A virus, responsible for acute respiratory infections in humans and animals, can be deadly. The virus kills half a million people each year. Scientists from the University of Geneva have identified how the virus infiltrates cells to cause infection. They discovered that the virus binds to a receptor on the surface of the cell and hijacks the iron transport mechanism to start infecting them. Still, by blocking the receptor involved, the researchers found that they could significantly reduce the virus’s ability to invade cells. This research paves the way for new strategies to counteract the virus and could be the first step towards identifying a potential treatment for influenza infections.
The Influenza virus is notorious for its mutation abilities and is therefore hard to detect and seal off. Experts already knew that the virus stuck to sugar structures on the cell surface before rolling along to find a suitable entry point into the host cell. However, until recently, scientists did not know which protein marked that entry point or how it favored virus entry. According to Mirco Schmolke, Associate Professor at the Department of Microbiology and Molecular Medicine and at the Geneva Center for Inflammation Research (GCIR) of the UNIGE Faculty of Medicine, this research “reveals the protein involved in marking that entry point.”
A receptor as the key to infection
Schmolke’s team first identified proteins on the cell surface situated next to viral hemagglutinin, one of the proteins that the Influenza A virus uses to enter the host cell. One protein, in particular, stood out, known as the transferrin receptor 1. This receptor works like a revolving door in the cell and supports iron molecules’ transportation into the cells, which are critical for many physiological functions.
The team found that “The influenza virus takes advantage of the continuous recycling of the transferrin receptor 1 to enter the cell and infect it,” and by replicating this phenomenon, the researchers “were able to inhibit virus replication in mice and human lung cells.”
Inhibiting this mechanism
The research team achieved this by inhibiting the transferrin 1 receptor using a chemical molecule. “We successfully tested it in human lung cells, in human lung tissue samples, and in mice with various viral strains,” says Béryl Mazel-Sanchez, a former postdoctoral researcher in Mirco Schmolke’s laboratory and the first author of the paper. ”In the presence of this inhibitor, the virus replicated much less. .”
Our discovery was made possible by excellent collaboration within the Faculty of Medicine, as well as with the University Hospitals of Geneva (HUG) and the Swiss Institute for Bioinformatics (SIB),” the authors add. In addition to the transferrin 1 receptor, scientists have identified 30 other proteins whose role in the influenza A entry process has not yet been deciphered.
Expanding on the topic: A Breakthrough in the Fight Against Influenza
The 1918 influenza pandemic remains one of the deadliest pandemics to have ever occurred, killing approximately 20-50 million people worldwide. Influenza is a viral disease that affects both humans and animals. In humans, it leads to respiratory infections that can cause severe disease or death. Although vaccines are effective in preventing influenza infections, mutations in the influenza virus make it hard for vaccine manufacturers to keep up with the changing strain patterns.
This limitation has made finding a universal influenza vaccine challenging, making treatments for the Influenza A virus inadequate. While Antiviral drugs such as Tamiflu can decrease the severity of the illness, the drug is not always effective, and the virus can develop new ways to mutate, making the treatment futile.
The study carried out by the team from the University of Geneva marks a promising breakthrough in the fight against influenza infections. The study identified a protein receptor responsible for the Influenza virus’s entry point into host cells. The researchers found that by blocking this receptor, they could significantly reduce the virus’s ability to invade cells.
The study also highlights the potential of cancer therapies based on transferrin receptor inhibition developed and tested in treating Influenza A. Although the virus uses a combination of various receptors in its entry process, blocking the transferrin 1 receptor could become a promising strategy in treating Influenza viruses in humans and potentially animals.
Fighting future pandemics that involve Influenza A or B viruses requires an approach that is both effective and practical. To this end, further research and development of treatments that identify previously undiscovered entry points are needed. Scientists can work towards developing a universal vaccine to combat Influenza infections, and with the discovery of this protein receptor pathway for Influenza, they may have made a significant breakthrough in disease management.
Summary
The Influenza A virus causes acute respiratory infections that claim half a million lives annually worldwide. A team of experts from the University of Geneva identified how the Influenza A virus manages to penetrate cells to infect them. They found that the virus hijacks the iron transport mechanisms to start infecting them by binding to a receptor on the cell surface. By blocking the transferrin 1 receptor involved, the research team was able to significantly reduce the virus’s ability to invade cells. The research findings highlight a vulnerability in the virus that researchers can exploit to counteract the infection. Although transferrin 1 receptor blockade is far from clinical application, this discovery is a promising step towards finding a treatment for Influenza virus infections.
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Influenza epidemics, caused by influenza A or B viruses, cause an acute respiratory infection. They kill half a million people around the world every year. These viruses can also wreak havoc in animals, as in the case of bird flu. A team from the University of Geneva (UNIGE) has identified how the influenza A virus manages to penetrate cells to infect them. By binding to a receptor on the cell surface, it hijacks the iron transport mechanism to start its infection cycle. By blocking the receptor involved, the researchers were also able to significantly reduce its ability to invade cells. These results, published in the journal PNAShighlights a vulnerability that could be exploited to combat the virus.
Influenza viruses pose a significant risk to human and animal health. Their mutation potential makes them particularly elusive. “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 surface of the host cell marked this entry point and how they favored virus entry,” explains Mirco Schmolke, Associate Professor at the Department of Microbiology and Molecular Medicine and at the Geneva Center for Inflammation. Research (GCIR) of the UNIGE Faculty of Medicine, who directed this work.
A receptor as the key to infection
The scientists first identified cell surface proteins present in close proximity to viral hemagglutinin, the protein used by the influenza A virus to enter the cell. One of these proteins stood out: the transferrin receptor 1. This acts like a revolving door that transports 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,” explains Béryl Mazel-Sanchez, a former postdoctoral researcher in the Mirco Schmolke laboratory and first author of this paper. “To confirm our discovery, we genetically engineered human lung cells to either delete the transferrin 1 receptor or, conversely, overexpress it. By deleting it in cells normally susceptible to infection, we prevented the entry of influenza A. Conversely, by overexpressing it in cells normally resistant to infection, we made them easier to infect.”
inhibiting this mechanism
The research team then succeeded in reproducing this mechanism by inhibiting the transferrin 1 receptor using a chemical molecule. “We successfully tested it in human lung cells, in human lung tissue samples, and in mice with various viral strains,” says Béryl Mazel-Sanchez. ”In the presence of this inhibitor, the virus replicated much less. However, given its potentially oncogenic characteristics, this product cannot be used to treat humans.” On the other hand, anticancer therapies based on transferrin receptor inhibition are under development and could also be interesting in this context.
“Our discovery was made possible by excellent collaboration within the Faculty of Medicine, as well as with the University Hospitals of Geneva (HUG) and the Swiss Institute for Bioinformatics (SIB),” the authors add. In addition to the transferrin 1 receptor, scientists have identified 30 other proteins whose role in the influenza A entry process has not yet been deciphered. In fact, it is likely that the virus uses a combination involving other receptors. “Although we are still far from a clinical application, transferrin 1 receptor blockade could become a promising strategy to treat influenza virus infections in humans and potentially in animals.”
https://www.sciencedaily.com/releases/2023/05/230531102006.htm
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