Published in Nature Microbiology, the study used a specialized version of cross-linking mass spectrometry (XL-MS) — a technique that chemically "freezes" protein interactions inside living cells — to capture the first large-scale map of direct contacts between influenza A virus proteins and human host proteins. Unlike previous methods that required breaking cells open (which causes proteins to mingle artificially), XL-MS preserves the native cellular environment, allowing researchers to see which interactions actually happen during infection.
The team identified two major hijacking strategies. First, they tracked how hemagglutinin — the spike protein the virus uses to enter cells — moves through the host's internal transport network. They discovered that the virus commandeers specific host proteins to help fold and modify hemagglutinin correctly, effectively turning the cell's quality-control machinery into a viral assembly line. Second, the virus dismantles structures called paraspeckles — nuclear bodies involved in gene regulation — by targeting key structural proteins. Destroying these paraspeckles frees up cellular resources for viral replication.
To model how viral and host proteins actually fit together, the researchers used a modified version of AlphaFold, the Nobel Prize-winning AI for protein structure prediction. By feeding the XL-MS cross-linking data directly into AlphaFold, the model could predict the three-dimensional architecture of virus-host protein complexes — including complexes that are notoriously difficult to predict because viruses and hosts evolved separately.
"Our work provides a new way to study flu-host interactions in their native context and with structural insight," said Jan Kosinski, Group Leader at EMBL Hamburg. "The current results are a snapshot of a moment during infection, and it opens the door to studying flu-host interactions across the entire infection cycle." The findings could reveal new targets for antiviral drugs and vaccines, particularly for the influenza A subtypes that pose the greatest pandemic risk, including H1N1 and H5N1.
Knowledge takeaway: EMBL researchers used cross-linking mass spectrometry inside intact infected cells to map 1,000+ virus-host protein contacts for the first time; the influenza A virus hijacks host protein folding machinery and dismantles nuclear paraspeckles to replicate; AlphaFold structural modeling guided by experimental cross-linking data revealed how viral and human proteins physically fit together, opening new avenues for drug design.