For the first time, scientists have produced a large-scale map showing in precise detail how the influenza A virus rewires the proteins inside an infected human cell to replicate itself, and the map reveals a hijacking strategy that no one had seen before. Researchers at EMBL Hamburg and collaborators at the Leibniz Research Institute for Molecular Pharmacology, Charité Berlin, and other institutions published their findings on July 20, 2026, in Nature Microbiology, describing how the flu virus commandeers the cell's internal machinery through two distinct strategies, including the dissolution of small nuclear structures called paraspeckles in a way that appears to serve the virus's reproductive needs.
The map is the most structurally detailed record ever made of how influenza A directly interacts with human proteins inside intact infected cells, providing a foundation that researchers say could support the design of new antiviral drugs and more effective vaccines.
Why This Matters
Seasonal influenza kills up to 650,000 people globally each year and causes serious illness in 3 to 5 million more, according to the World Health Organization. The United States alone sees between 12,000 and 52,000 flu deaths annually, per CDC estimates. Despite decades of research, antiviral options for flu remain limited to a handful of drugs, most targeting only a small number of the virus's own proteins. The challenge has been that the flu virus is highly variable and mutations that help it escape antiviral drugs emerge quickly.
One strategy for developing better drugs is to target the human proteins the virus depends on, rather than the virus's own proteins. Those human proteins change far more slowly through evolution, making them potentially more stable targets. But to identify which human proteins the virus most critically depends on, scientists need to know exactly how and where the virus physically interacts with them inside an infected cell. That is precisely what this new molecular map provides.
What We Know So Far
The research team used a technique called in-cell cross-linking mass spectrometry, which allows scientists to chemically "freeze" protein-protein contacts as they occur inside a living, intact cell and then analyze which proteins were touching which at the moment of infection. Crucially, this technique captures interactions inside the cell in real time, rather than in isolated cell-free preparations that may not reflect true infection biology.
The approach, developed and customized for this study, involved cross-linking mass spectrometry experiments at Charité in Berlin, glycoproteomics analyses at the EMBL Proteomics Core Facility, AlphaFold structural modeling on the EMBL Compute Cluster, and microscopy imaging at CSSB's Advanced Light and Fluorescence Microscopy Facility. The combination of methods gave the team enough structural resolution to model how the interacting proteins physically fit together, not just which ones were touching.
The map revealed two major hijacking strategies.
The first involves haemagglutinin, the protein on the flu virus's surface that it uses to bind and enter host cells. The researchers traced how haemagglutinin moves through the cell's internal processing and transport system after infection. This revealed that host proteins, some with previously unknown functions in flu infection, help the virus correctly fold and chemically modify haemagglutinin so it functions properly. Identifying these host helpers opens them as potential drug targets.
The second discovery was entirely unexpected: paraspeckles. Paraspeckles are small, droplet-like structures inside the cell nucleus that are made of RNA and proteins. They function as storage compartments for certain RNA-binding proteins. The researchers found that influenza A infection caused paraspeckles to dissolve across every cell line and every flu strain they tested. When the paraspeckles broke apart, they released RNA-binding proteins that had been stored inside them, and the virus appears to use those released proteins to support its own replication.
"What surprised us most was the paraspeckles," said Iuliia Kotova, Ph.D., former predoctoral fellow at EMBL Hamburg, currently at ETH Zurich, and first author of the paper, according to ScienceDaily. "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."
What the Paraspeckle Discovery Means
The consistent dissolution of paraspeckles across multiple cell lines and multiple influenza strains is a significant finding because it suggests this is not an incidental phenomenon but a deliberate biological program the virus executes. If that is confirmed in further research, paraspeckle components and the proteins they contain become candidates for antiviral drug development.
Senior author Jan Kosinski, Ph.D., group leader at EMBL Hamburg and the Centre for Structural Systems Biology, noted a possible second benefit for the virus beyond protein capture. "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," Kosinski told ScienceDaily.
If paraspeckle disruption both provides the virus with useful proteins and disables part of the cell's antiviral defenses simultaneously, this hijacking strategy would be serving the virus's interests on two fronts at once. The researchers emphasized this is still being investigated and the evidence for the defensive-disruption benefit is described as early-stage.
Where This Research Stands in the Clinical Pathway
This is foundational laboratory science: mapping what happens during infection, not testing a drug in human patients. The map provides new hypotheses for drug targeting, but translating those hypotheses into approved antiviral treatments requires years of drug development, preclinical testing, and multiple phases of clinical trials. No drug targeting paraspeckles or the specific host proteins identified in this study has entered human trials.
The researchers note that the cross-linking mass spectrometry approach used here could be extended to study other viruses, not only influenza, making it a general tool for future virology research. That scalability adds significance beyond the flu findings alone.
What Doctors and Experts Say
"Our work provides a new way to study flu-host interactions in their native context and with structural insight," said Kosinski, as quoted in Genetic Engineering and Biotechnology News. "We identified host factors linked to the maturation of distinct glycoforms of the viral surface glycoprotein haemagglutinin through the membrane-bound endoplasmic reticulum-Golgi system."
The study was funded through European research infrastructure programs and relied on shared scientific infrastructure across multiple institutions. The published paper's title is "Mapping in-cell protein contact sites reveals hijacking of paraspeckles during influenza A virus infection," and it concluded that the findings "uncover" previously unknown mechanisms the flu virus uses to exploit host cells, positioning several of the identified host-virus interaction points as potential drug discovery targets.
What the Evidence Shows and What It Does Not
MedicalDaily Evidence Check
- Study type: Mechanistic laboratory research using in-cell cross-linking mass spectrometry; not a drug trial or human study
- Published in: Nature Microbiology; doi: 10.1038/s41564-026-02416-1; published July 20-21, 2026
- Institutions: EMBL Hamburg (lead); Leibniz Research Institute for Molecular Pharmacology (FMP); Charité Berlin; ETH Zurich; CSSB
- Senior author: Jan Kosinski, Ph.D., group leader, EMBL Hamburg and CSSB
- First author: Iuliia Kotova, Ph.D., ETH Zurich (former EMBL Hamburg)
- Key finding 1: Detailed map of how influenza A uses host proteins to fold and process haemagglutinin; some host proteins with previously unknown roles identified
- Key finding 2: Flu infection consistently dissolves paraspeckles in the cell nucleus across multiple cell lines and flu strains, releasing RNA-binding proteins the virus may use for replication
- What it shows: The first large-scale structural map of virus-host protein contacts inside intact influenza-infected cells
- What it does not prove: That blocking paraspeckle dissolution or any specific host protein contact would be safe or effective as an antiviral strategy in humans; drug development work based on these targets has not yet begun
- What readers should know: This research advances understanding of flu biology and opens new drug targets. It does not change current flu prevention or treatment guidance. Annual flu vaccination remains the most important individual protective action.
Who Should Pay Attention?
This research is most immediately relevant to:
- Virologists and influenza researchers studying flu-host interactions
- Pharmaceutical researchers exploring host-directed antiviral strategies
- Public health scientists interested in the mechanistic basis for why current antivirals have limited efficacy
- Science-engaged general readers who follow virology and infectious disease research
For the general public, this research does not change flu prevention recommendations.
Symptoms and Flu Warning Signs to Know
The influenza symptoms this research ultimately addresses are the same ones every flu season produces:
- Sudden onset of fever (often 100 to 104 degrees F) and chills
- Severe muscle aches and body pains
- Extreme fatigue
- Dry cough
- Headache
- Sore throat
- Runny or stuffy nose
- Some people, particularly children, may experience vomiting and diarrhea
Flu typically arrives more abruptly than a common cold, with more intense systemic symptoms. Antiviral drugs like oseltamivir (Tamiflu) are most effective when started within 48 hours of symptom onset. High-risk individuals should contact a health care provider promptly at the first sign of flu symptoms.
What You Can Do Now
- Get your annual flu vaccine. Flu vaccination remains the single most effective measure for reducing flu-related illness and death. Updated vaccines are available every fall.
- If you develop flu symptoms and are in a high-risk group (adults 65 and older, pregnant people, young children, or immunocompromised individuals), contact a health care provider promptly to discuss whether antiviral treatment is appropriate.
- Wash hands frequently during flu season and avoid close contact with sick individuals.
- This research does not indicate any change in flu treatment currently available or any new product to seek out. Watch for future updates in antiviral development; any drug based on these findings is years from clinical use.
Cost and Access: What Patients Should Know
Annual flu vaccines are covered under most insurance plans and Medicare as a preventive care benefit at no cost. For uninsured patients, flu vaccines are available at low or no cost through local health departments, federally qualified health centers, and pharmacy programs. Antiviral medications for flu treatment (oseltamivir, baloxavir) require a prescription and are covered by most insurance plans; cost-assistance options are available for uninsured patients through manufacturer programs.
What Happens Next
The EMBL Hamburg team plans to apply the same in-cell cross-linking mass spectrometry technique to study other viruses, expanding the map-based approach beyond influenza. The paraspeckle findings specifically are expected to generate follow-up research examining whether blocking paraspeckle dissolution or protecting the proteins released from them affects viral replication and whether any existing drugs interfere with this process. MedicalDaily will report on drug development advances based on this molecular map as they emerge.
The Bottom Line
EMBL Hamburg scientists have produced the most detailed map ever made of how influenza A virus interacts with human proteins inside intact infected cells, and the map revealed a previously unknown strategy: the flu virus consistently dissolves tiny nuclear structures called paraspeckles across every cell line and every strain tested, releasing proteins it appears to use for replication. The discovery opens new drug targets for antiviral development. It does not change current flu prevention or treatment guidance. Annual vaccination remains the most important step anyone can take.
