Researchers at EMBL Hamburg and the Leibniz Research Institute for Molecular Pharmacology (FMP) have developed a new method to map influenza A protein interactions inside intact human cells. By combining cross-linking mass spectrometry (XL-MS) with structural modeling via AlphaFold, the team captured how the virus hijacks host cell machinery, offering a potential blueprint for future antiviral drug development.
Mapping Viral Hijacking Inside Intact Cells
Influenza A remains a significant global health burden, causing between 3 and 5 million severe illnesses and up to 650,000 deaths annually, according to data cited by the research team. Traditional laboratory methods often require scientists to break cells open, a process that can destroy delicate protein connections or create artificial interactions that do not occur in nature. To solve this, Boris Bogdanow, then at FMP Berlin, and his colleagues utilized a specialized version of XL-MS to study these interactions in their native environment.
This workflow allows researchers to observe the interface between viral and human proteins directly. By pairing this data with a modified version of AlphaFold, the team could model the structural positioning of proteins during infection. According to Jan Kosinski, Group Leader at EMBL Hamburg and CSSB, this approach provides a “snapshot” of the infection cycle, revealing structural details that were previously difficult to predict.
Did you know?
The 1918 Spanish Flu pandemic was driven by influenza A. Understanding how these viruses redirect host molecular systems is a key goal for researchers aiming to prevent future pandemic outbreaks.
Hemagglutinin and the Cellular Transport Network
The study, published in Nature Microbiology, identified two primary strategies influenza A uses to control host cells. The first involves hemagglutinin, a surface protein the virus uses to enter human cells. Once inside, the virus manipulates the cell’s internal transport network—the system responsible for folding and modifying proteins.
The research team observed that influenza A recruits specific human proteins to assist in folding hemagglutinin correctly. Some of these host proteins had previously been poorly understood, but the new mapping technique clarified their role in facilitating the production of new viral particles. By identifying these “helper” proteins, scientists may be able to target them to inhibit viral replication.
The Dissolution of Nuclear Paraspeckles
A second discovery centered on the nucleus of the cell. The researchers found that influenza A infection causes paraspeckles—small, droplet-like structures—to dissolve. When these structures break apart, they release RNA-binding proteins that the virus may repurpose for its own replication.
“Watching these tiny organelles in the nucleus dissolve, consistently across every cell line and every flu strain we tested, told us this isn’t a side effect of infection—it might be a strategy,” said Iuliia Kotova, the study’s first author and former predoctoral fellow at EMBL Hamburg. Beyond assisting the virus, the dissolution of these structures may also dampen the cell’s natural antiviral defenses, as paraspeckles are known to contribute to cellular stress responses.
Researchers interested in structural biology can look for studies utilizing the EMBL Compute Cluster and specialized microscopy facilities like the CSSB’s Advanced Light and Fluorescence Microscopy (ALFM) to see how cross-disciplinary technology is accelerating drug target identification.
Future Trends in Pandemic Preparedness
The methodology developed by the EMBL and FMP team is designed to be adaptable. While the current study focused on a laboratory-adapted strain of influenza, the researchers suggest this “mapping in context” approach could be applied to viruses with higher pandemic potential, such as H5N1.
As the scientific community continues to refine AlphaFold modeling and mass spectrometry, the ability to see how viruses interact with human cells in real-time will likely become a cornerstone of drug discovery. By mapping these interaction networks, scientists aim to identify “actionable targets” that could lead to more effective vaccines and therapies. For more information on emerging trends in virology, explore the latest publications from EMBL.
Frequently Asked Questions
How does influenza A hijack human cells?
Influenza A uses viral proteins to redirect host cell systems. Specifically, it manipulates protein-folding compartments for surface proteins like hemagglutinin and dissolves nuclear structures called paraspeckles to release proteins needed for viral replication.
Why is mapping proteins in intact cells important?
Breaking cells open can distort protein interactions or cause false connections. Mapping within intact cells ensures that the data reflects the actual biological processes occurring during an active infection.
Can this research help create new flu vaccines?
Yes. By identifying the specific human proteins the virus relies on to survive and replicate, researchers can better understand how to block these interactions, potentially leading to new antiviral drugs and more effective vaccine targets.
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