New Insights into Influenza A Virus Receptors and Potential Treatments

Medical News: Influenza A virus (IAV) is one of the most dangerous and widely studied viruses in the world. It is responsible for annual flu outbreaks, causing millions of infections and thousands of deaths worldwide. The virus has an extraordinary ability to evolve and adapt, making it a constant threat to public health. Scientists from the Smorodintsev Research Institute of Influenza in Russia and the Almazov National Research Centre have conducted extensive research into the way this virus enters human cells and how it can be stopped. This Medical News report highlights their recent findings on how IAV attaches to human cells and explores potential treatments that could inhibit the infection process.


Schematic representation of the influenza A virus adsorption in the respiratory tract, showing the receptors/co-receptors involved in the attachment of the virus to the host cells. The repertoire of receptors varies depending on the type of infected cells (epithelial cell/macrophage, DC/NK cell). After the initial SIA-dependent attachment of the virus to the cell surface, viral particles roll to lipid rafts containing several protein receptors and co-factors of the IAV entry. Possible functional interplay between them remains elusive. Known signaling pathways triggered by receptor molecules upon IAV binding are indicated. Abbreviations: DC—dendritic cell, NK—natural killer cell, MHC II—main histocompatibility complex class II, EGFR—Epidermal growth factor receptor, TfR1—Transferrin receptor 1, CEACAM6—CEA Cell Adhesion Molecule 6, TLR4—toll-like receptor 4, Cav1.2—Voltage-dependent Ca2+ channel, mGluR2—Metabotropic glutamate receptor subtype 2, FFAR2—free fatty acid receptor 2, MMR— macrophage mannose receptor, MGL1—macrophage galactose-type lectin 1, HA—hemaggtlutinin, NA—neuraminidase, PI3K—phosphatidylinositol 3-kinase, FAK—focal adhesion kinase, PLC-γ1—phosphoinositide-specific phospholipase γ1, KCa1.1— potassium calcum-activated channel subfamily M alpha 1.

The Mechanism of Influenza A Virus Attachment
The first step in the influenza infection process is the virus's attachment to the surface of human cells. The virus has special proteins on its outer shell called hemagglutinin (HA) and neuraminidase (NA). These proteins allow it to recognize and bind to receptors on human cells. The most well-known receptor for IAV is a molecule called sialic acid. However, the researchers have now identified many additional receptors and co-receptors that influenza A virus can use to enter cells. These include receptor tyrosine kinases, ion channels, C-lectins, antigen-presenting molecules, and pattern-recognizing receptors. This discovery suggests that the virus has multiple ways to infect cells, making it more adaptable and harder to block completely.
 
The researchers also studied how the virus uses these different receptors. Some receptors seem to work together, enhancing the virus's ability to enter cells, while others might compete with each other. Understanding this interplay is crucial for developing new antiviral drugs that can effectively block the virus at the very first stage of infection.
 
New Strategies to Stop the Virus
With the identification of new receptors, researchers are now looking at novel ways to prevent the virus from entering cells. One promising approach is the use of small molecules that can block these receptors. Some of these molecules are already used to treat other diseases and could be repurposed as antiviral drugs. For example, inhibitors of receptor tyrosine kinases, which are currently used in cancer treatments, have shown potential in preventing IAV infection. Similarly, molecules that disrupt lipid rafts in cell membranes - areas where the virus gathers before entering - could also serve as effective treatments.
 
Another promising strategy is the use of nanotechnology. Scientists are developing nanoparticles that can trap the virus before it reaches human cells. These nanoparticles mimic the natural receptors that the virus binds to, but instead of allowing the virus to enter a cell, they capture and neutralize it. This could be a groundbreaking way to prevent infections, especially during flu outbreaks.
 
The Role of Enzyme Inhibitors and Therapeutics
Several enzyme inhibitors have been identified that can stop the virus from successfully infecting cells. One group of inhibitors targets the phosphatidylinositol 3-kinase (PI3K) pathway, which the virus exploits to enter human cells. Inhibiting this pathway prevents the virus from penetrating the cell membrane. Drugs like wortmannin and LY294002, originally developed for cancer treatments, have shown promising results in blocking IAV entry.
 
Another class of drugs that could be repurposed for influenza treatment is the group of Akt inhibitors. Akt is a crucial protein in cell survival and viral replication. The drug MK2206, initially designed for cancer therapy, has demonstrated antiviral properties by blocking Akt signaling and reducing IAV replication.
 
Similarly, the focal adhesion kinase (FAK) pathway, another key player in the virus’s entry process, has also been targeted successfully. FAK inhibitors such as Y15 and Defactinib have been investigated for their anti-cancer properties, but recent studies suggest that they could also interfere with the ability of the influenza virus to attach and enter cells. In experiments with mice, inhibiting FAK with Y15 resulted in lower viral loads and increased survival rates, demonstrating its potential as a therapeutic option for influenza infections.
 
The p38 mitogen-activated protein kinase (p38 MAPK) pathway has also been identified as an essential signaling pathway for influenza virus entry and replication. Small molecules like SB203580, which selectively inhibit p38 MAPK, have been studied for their potential to block viral infection at an early stage. Another compound, VX-702, originally developed for inflammatory diseases, has shown effectiveness in reducing viral replication by targeting p38 MAPK.
 
Additionally, host-directed therapies targeting calcium channels are being explored. The calcium channel blocker diltiazem, commonly prescribed for high blood pressure, has been found to significantly reduce IAV infection by interfering with calcium-dependent signaling pathways that the virus exploits for entry and replication. This suggests that existing cardiovascular drugs could be repurposed to combat influenza.
 
Future Directions for Influenza Research
The new findings indicate that combating influenza A virus requires a multi-faceted approach. Blocking just one receptor or pathway may not be enough to prevent infection, given the virus's ability to use multiple entry mechanisms. This suggests that future antiviral treatments should target several cellular components at once. Researchers are also investigating whether combination therapies, using multiple inhibitors together, could offer a more effective solution.
 
Another important area of research is vaccine development. While current flu vaccines primarily target hemagglutinin and neuraminidase, new vaccines could be designed to target some of the newly discovered receptors. By training the immune system to recognize and attack these key entry points, scientists could develop more effective and long-lasting flu vaccines.
 
Additionally, advances in genetic engineering may help create antiviral treatments that can be tailored to specific flu strains. By analyzing the genetic makeup of different IAV strains, researchers can identify which receptors a particular strain prefers to use. This could lead to personalized treatments that are more effective in stopping specific outbreaks.
 
Conclusions
The study findings shed new light on how influenza A virus infects human cells. Their findings reveal that IAV uses a much wider range of receptors than previously known, which makes it a highly adaptable and resilient pathogen. However, this research also highlights new opportunities for treatment and prevention.
 
Targeting multiple viral entry mechanisms simultaneously appears to be the most promising strategy for future antiviral drug development. Small molecules that block receptor activity, enzyme inhibitors that prevent virus penetration, and nanotechnology-based virus traps are all showing potential in laboratory studies. The re-purposing of existing drugs, particularly those used for cancer and metabolic diseases, offers a fast-track route for developing new flu treatments.
 
These findings also reinforce the need for continued investment in vaccine research. By developing vaccines that target not only the viral surface proteins but also the receptors and pathways used for infection, scientists may be able to create longer-lasting and more effective flu immunizations.
 
The study findings were published in the peer-reviewed journal: Microbiological Research.
https://www.mdpi.com/2036-7481/16/2/37
 
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