Scientists at EMBL Hamburg, together with the Leibniz Research Institute for Molecular Pharmacology, created a very detailed picture of how influenza A changes an infected human cell.
Each year, seasonal flu makes 3‑5 million people very sick and can cause up to 650 000 deaths worldwide. Influenza A also caused historic pandemics, like the 1918 Spanish flu.
When the virus enters a cell, it releases RNA that carries the recipe for a few viral proteins. Those proteins spread through the cell, redirecting its normal machinery to make new virus particles.
Why Mapping the Flu Inside Whole Cells Matters
Understanding exactly which viral proteins touch which human proteins can help design better flu vaccines and antiviral drugs. Researchers needed to see these contacts inside intact cells, not in broken‑apart samples.
The new study is the first to map direct contacts between flu proteins and human proteins on a large scale while the cell stays whole. The level of detail is good enough to model how the two proteins might fit together.
“Our work gives a fresh way to study flu‑host interactions in their natural setting, with structural insight,” said Jan Kosinski, group leader at EMBL Hamburg.
Overcoming a Big Experimental Hurdle
Finding protein‑protein interactions during an active infection is hard. Old methods required breaking the cell open first, which can create false contacts and lose weak or short‑lived ones.
To solve this, the team used a special version of cross‑linking mass spectrometry (XL‑MS) created by collaborators at the FMP in Berlin. This technique captures fleeting contacts inside living, intact cells.
“XL‑MS lets us lock protein pairs together inside the infected cell and also tells us how they are arranged,” explained Boris Bogdanow, junior group leader at the Charité Institute of Virology.
Adding AlphaFold Modeling
The scientists combined the XL‑MS data with computer‑based structural modeling. They used a tweaked AlphaFold system, the Nobel‑prize‑winning tool for predicting protein shapes.
By feeding the experimental distance data into AlphaFold, the model knew which parts of the viral and human proteins sit close to each other. This made the predicted virus‑host structures more reliable.
Two Ways Flu Hijacks the Cell
The study, published in *Nature Microbiology*, uncovered two main tricks used by influenza A.
- Hijacking hemagglutinin. Hemagglutinin is a protein on the virus surface that helps it attach to and enter cells. The researchers followed this protein as it moved through the cell’s folding and modification stations. Several human proteins helped the virus fold hemagglutinin correctly, and some of those host proteins were previously poorly understood.
- Breaking apart nuclear paraspeckles. Paraspeckles are tiny droplet‑like structures inside the nucleus. Flu infection made these structures dissolve, releasing RNA‑binding proteins that the virus can then use for its own replication. Losing paraspeckles may also weaken the cell’s stress response and antiviral defenses.
Teamwork Across Three Institutes
The project combined expertise from three places. Cross‑linking work happened at Charité in Berlin, glycoproteomics at the EMBL Proteomics Core, AlphaFold modeling on the EMBL compute cluster, and microscopy at the CSSB Advanced Light and Fluorescence Microscopy Facility.
A Blueprint for Future Virus Research
By mapping virus‑host contacts inside whole cells, scientists now have a clearer view of how a virus takes over human machinery. The approach can be applied to other viruses, including those with pandemic potential such as H5N1.
“Our method—combining in‑cell cross‑linking, structural modeling, and targeted cell‑biology follow‑up—should work for many viruses,” said Kosinski.