How the Flu Virus Hijacks a Human Cell From the Inside
A live-cell interaction map revealed how influenza dismantles host defenses and redirects cellular machinery.
Defeating an invading enemy requires knowing their exact battle strategy before they launch an attack.
To understand how this concept applies to viral infections, a group of researchers at the European Molecular Biology Laboratory (EMBL) Hamburg tracked interactions between a flu virus and a human cell in real time.
Their new map captures thousands of physical contacts, revealing, for the first time, how the virus systematically disarms host-cell defenses.
How a virus hijacks the human cell from within
Every year, influenza A seasonal strains cause up to 650,000 deaths and 3–5 million severe illnesses worldwide. This virus has driven devastating pandemics, including the 1918 Spanish Flu.
When the virus enters a human cell, it releases its genetic material to spread viral proteins and hijack the host's internal machinery, relying on a web of complex protein interactions.
To stop this process, scientists need to see exactly how these proteins interact; however, traditional methods fall short. Older techniques require physically breaking the cells open, which destroys the natural spatial architecture and results in the loss of fragile or location-specific connections. This process can also cause artificial protein pairings inside the test tube.
In the new study, the team aimed to map the physical contacts between the virus and the human cell at scale, using intact, living cells for the first time. By capturing these interactions in their native cellular environment, they attempted to generate structural insights and predictive models that show how viral and human protein complexes physically fit together.
Mapping the direct contacts between a virus and a human cell
The team mapped the interactions using a method called structural host-virus interactome profiling, trapping protein contacts within a 40 Å distance constraint.
“This is when we learned that our collaborators—Dr. Boris Bogdanow and Prof. Fan Liu—at FMP Berlin had developed a specialized version of cross-linking mass spectrometry (XL-MS), a long-established technique for mapping protein contacts, tailored specifically to virus-infected cells,” said co-corresponding author Dr. Jan Kosinski, a group leader at EMBL Hamburg.
“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 Bogdanow, a junior research group leader at Charité – Universitätsmedizin Berlin.
The experimental data was integrated into a modified version of AlphaFold.
“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 Kosinski. “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.”
Cellular validation confirmed 13,588 unique cross-links, revealing 198 distinct viral-host pairs.
The resulting map led to two biological steps for viral entry and attack.
First, the team used the map to trace the viral protein hemagglutinin, finding that the virus systematically exploited the human cell’s internal transport network to fold and mature the vital entry protein.
Hemagglutinin
A protein found on the surface of the influenza virus that acts like a microscopic key, allowing the virus to latch onto and enter a human cell.
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The map then revealed the virus was able to completely dissolve nuclear paraspeckles—organelles used in host stress responses—within four to eight hours of infection.
“What surprised us most was the paraspeckles,” said first author Dr. Iuliia Kotova, a postdoctoral researcher at ETH Zürich. “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.”
This method of destruction relied on a three-pronged attack: viral proteins bound to cellular targets while viral enzymes degraded host RNA and blocked gene expression.
“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 defense response,” added Kosinski.
By breaking down these compartments, the virus frees trapped human cell proteins and repurposes them to accelerate its own replication.
Future treatments for viral infections
The study offers a versatile framework to study how pathogens interact with host organisms.
“Our work provides a new way to study flu-host interactions in their native context and with structural insight,” said Kosinski. “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.”
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“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,” Kosinski added.
By defining the exact physical points where a virus attaches to a human cell, the dataset provides targets for designing new antiviral drugs and vaccines.
However, the experimental window focused on late-stage infection events between 5–14 hours, missing early-stage dynamics such as initial replication activity. Some captured cellular networks also showed high redundancy, meaning that blocking a single gene did not always stop the virus.
Future research should look to capture earlier stages of infection and across a diverse range of viruses.
“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,” Bogdanow added.
Reference: Kotova I, Mühlberg L, Gilep K, et al. Mapping in-cell protein contact sites reveals hijacking of paraspeckles during influenza A virus infection. Nat Microbiol. 2026. doi: 10.1038/s41564-026-02416-1
This article is a rework of a press release issued by the European Molecular Biology Laboratory. Material has been edited for length and content.
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