Seasonal influenza may feel familiar, but the virus behind it, influenza A, is a master manipulator. Every year, it causes serious illness in millions and claims up to 650,000 lives worldwide. What makes it so dangerous is its ability to infiltrate human cells and rewire them to churn out more viruses.
Now, researchers at EMBL Hamburg and the Leibniz Research Institute for Molecular Pharmacology (FMP) have mapped this cellular takeover in unprecedented detail. Their study, published in Nature Microbiology, is the first to capture direct virus-host protein contacts inside intact infected cells, with enough structural resolution to model how the proteins fit together.
Ancient studies usually smashed cells before measuring protein interactions, leading to false positives or the loss of weak binding partners. The results were made possible when collaborators Boris Bogdanow and Fan Liu created an optimized version of cross-linking mass spectrometry (XL-MS) for use in cells infected with a virus.
“XL-MS allows us to capture protein-protein interactions directly in infected intact cells, while also providing structural information about how these interactions are happening,” said Bogdanow, now a Junior Research Group Leader at Charité – Universitätsmedizin Berlin.
By combining XL-MS with computational modeling using a modified AlphaFold, the team could predict how viral and human proteins physically fit together. “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,” explained Jan Kosinski, Group Leader at EMBL Hamburg.
The study revealed two striking ways influenza A manipulates host cells:
Haemagglutinin Processing
Haemagglutinin, the viral surface protein that enables entry into host cells, was traced through the cell’s internal transport system. Host proteins, some with previously unknown roles, were found to help fold and modify haemagglutinin, ensuring the virus can assemble correctly.
Paraspeckle Dissolution
Paraspeckles, tiny nuclear compartments, consistently dissolved during infection across all tested strains.
“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, first author and former EMBL fellow.
This not only frees RNA-binding proteins for viral replication but may also weaken the cell’s stress responses and antiviral defenses.
The work relied on shared infrastructure across Berlin and Hamburg, combining proteomics, microscopy, and computational modeling. Beyond influenza, the researchers believe their ‘mapping in context’ approach can be applied to other viruses, including those with pandemic potential like H5N1.
Kosinski summed up the broader vision: “While the exact host factors and mechanisms often differ from virus to virus, we think our overall approach – combining in-cell cross-linking, structural modeling, and targeted cell-biology follow-up to map native virus-host interactions at specific stages of infection, remains broadly applicable.”
Bogdanow added: “Although this study has focused on a lab-adapted strain, this study lays the groundwork to apply the methodology to viruses of potential pandemic relevance, such as H5N1, and for uncovering the interaction networks that support their multiplication in human cells.”
Studying how both influenza proteins and human cell machinery handshake at the molecular level, scientists have not only learned what allows these viruses to survive but also to flourish. A detailed map of how viruses hijack cells could help inform new therapies and vaccines to do a bit of the flu’s own sleight-of-hand against it.
