Scientists Uncover How Flu Virus Rewires Human Cells During Infection

Researchers have, for the first time, mapped how influenza A directly rewires infected human cells by tracking virus-host protein interactions inside intact cells. Published in Nature Microbiology, the study provides unprecedented structural insights into how the virus exploits cellular machinery, offering promising leads for the development of more effective antiviral drugs and vaccines.

First detailed map reveals virus-host interactions

A team of researchers from EMBL Hamburg, the Leibniz Research Institute for Molecular Pharmacology (FMP), Charité – Universitätsmedizin Berlin and collaborating institutions has produced the first large-scale structural map of direct interactions between influenza A proteins and human proteins inside infected cells.

Seasonal influenza is responsible for up to 650,000 deaths globally each year and causes severe illness in an estimated 3–5 million people. Influenza A has also triggered several pandemics, including the devastating 1918 Spanish Flu.

To uncover how the virus takes control of human cells, the researchers developed a customised experimental workflow that enabled them to observe protein interactions directly inside infected cells. Unlike previous techniques, the method captured short-lived and location-specific interactions while preserving the proteins' natural environment.

"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 and the Centre for Structural Systems Biology (CSSB), adding, "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 researchers employed a specialised version of cross-linking mass spectrometry (XL-MS), specifically adapted for virus-infected cells.

"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," explained Boris Bogdanow, now a Junior Research Group Leader at the Institute of Virology, Charité – Universitätsmedizin Berlin, adding, "This gives us insight into the interface between the virus and the human cell and may, through structural modelling, help identify actionable targets for future pharmaceutical interventions."

The team also combined XL-MS data with a modified version of AlphaFold, the artificial intelligence-based protein structure prediction tool, to understand how viral and human proteins physically interact.

"The key advantage of the modified AlphaFold approach is that it allowed us to feed our experimental cross-linking data directly into the structural modelling," Kosinski said, adding, "This tells the model which parts of the viral and host proteins are close to each other inside infected cells. This was especially useful for virus-host complexes, which are often difficult to predict reliably."

Scientists uncover two key viral strategies

The study identified two major mechanisms used by influenza A to commandeer infected cells.

Researchers traced how the virus's surface protein haemagglutinin moves through the host cell's transport and processing machinery, identifying human proteins that help fold and modify this critical viral protein during infection.

The team also discovered that influenza A infection causes paraspeckles—small droplet-like compartments inside the cell nucleus—to dissolve. This process releases RNA-binding proteins that the virus subsequently uses to replicate.

"What surprised us most was the paraspeckles," said Iuliia Kotova, first author of the study and currently at ETH Zurich, adding, "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."

Kosinski added, "There may also be a second benefit for the virus: some evidence suggests paraspeckles contribute to cellular stress responses and antiviral gene regulation, so disrupting them could also weaken parts of the cell's defence response."

Findings could aid future pandemic preparedness

The research relied on scientific infrastructure across multiple institutions, including cross-linking mass spectrometry experiments at Charité in Berlin, glycoproteomics analyses at the EMBL Proteomics Core Facility, AlphaFold modelling on the EMBL Compute Cluster, and microscopy imaging at CSSB's Advanced Light and Fluorescence Microscopy Facility.

The researchers believe the workflow can be extended beyond influenza to study other viruses and improve preparedness against future outbreaks.

"While the exact host factors and mechanisms often differ from virus to virus, we think our overall approach - combining in-cell cross-linking, structural modelling, and targeted cell-biology follow-up to map native virus-host interactions at specific stages of infection - remains broadly applicable," Kosinski said.

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."

(With inputs from ANI)