Scientists map how the flu virus rewires the human cell from the inside

Scientists have created the most detailed map yet of how the influenza A virus manipulates human cells from within, revealing intricate networks of protein interactions that enable the virus to hijack cellular processes for its replication. Researchers from EMBL Hamburg and the Leibniz Research Institute for Molecular Pharmacology (FMP) achieved this breakthrough using a novel method that captures protein interactions in intact infected cells, offering insights previously unattainable with traditional techniques. The findings, published in a recent study, show that the influenza A virus uses its RNA to produce specific proteins that interfere with the host cell’s normal functions. These viral proteins then exploit the cell's internal machinery to replicate and assemble new virus particles. Understanding these interactions is essential for developing improved antiviral drugs and vaccines, as it reveals potential targets for therapeutic intervention. Seasonal influenza is estimated to cause up to 650,000 deaths annually worldwide and leads to severe illness in millions. Influenza A, in particular, has triggered some of history's deadliest pandemics, such as the 1918 Spanish flu. The ability to track how the virus interacts with host proteins in real-time represents a major step forward in virology research. Traditional methods of studying protein interactions often required breaking apart the cell, which could distort or obscure certain interactions. However, the team employed a specialized form of cross-linking mass spectrometry (XL-MS), developed by researchers at FMP Berlin, allowing them to examine these interactions in intact cells. This technique enabled the detection of transient and spatially specific interactions that might otherwise go unnoticed. Jan Kosinski, a group leader at EMBL Hamburg and the Centre for Structural Systems Biology (CSSB), emphasized the significance of this approach. “Our work provides a new way to study flu-host interactions in their native context and with structural insight,” he stated. The initial findings represent a snapshot of the interaction dynamics during infection, opening the possibility to explore these interactions throughout the entire infection cycle. Boris Bogdanow, a researcher at the Institute of Virology, Charité, Universitätsmedizin Berlin, highlighted the importance of the XL-MS technique. “This allows us to capture protein-protein interactions directly in intact infected cells, while also providing structural information about how these interactions occur,” he noted. Such data can inform the design of pharmaceutical agents targeting these interactions. To further analyze the physical compatibility of interacting viral and human proteins, the researchers integrated their XL-MS results with computational models based on AlphaFold, a groundbreaking algorithm for predicting protein structures. By feeding experimental cross-linking data into these models, they could determine which regions of viral and host proteins come into proximity during infection. Kosinski described the benefit of this combined approach. “The key advantage of the modified AlphaFold approach is that it allowed us to feed our experimental cross-linking data directly into the structural modeling,” he said. This integration provided a clearer picture of the molecular interfaces formed between the virus and the host cell. The study identified numerous points of contact between viral and human proteins, each potentially representing a target for antiviral therapy. These findings offer a foundation for future research aimed at disrupting these interactions and preventing viral replication. As the understanding of these complex biological processes deepens, so too does the potential for innovative treatments against influenza and other viral diseases.