A team of researchers has achieved an unprecedented feat: creating a detailed map of how the influenza A virus remodels infected human cells.
Researchers from the European Molecular Biology Laboratory in Hamburg, in collaboration with scientists from the Leibniz Institute for Molecular Pharmacology Research in Berlin, relied on an advanced technique that enabled them to monitor interactions between proteins directly inside healthy cells, without the need to break them down as had been the case in previous studies, giving a more accurate picture of what actually happens during infection.
This study is of paramount importance, as seasonal influenza causes between 3 and 5 million severe illnesses worldwide annually and is associated with approximately 650,000 deaths. Furthermore, the influenza A virus has been responsible for numerous devastating pandemics, including the 1918 Spanish flu pandemic, which claimed millions of lives.
To develop more effective vaccines and antiviral drugs, experts need a precise understanding of how the virus takes control of the cell, identifying which viral proteins interact with human proteins, where these interactions occur, and how the virus uses them to support its replication.
Researchers faced a significant challenge in tracking these interactions during active infection because traditional methods required breaking down cells before measuring protein contacts. This could distort the true picture of what was happening inside the living cell, as weak or temporary interactions might disappear, or proteins that were originally separate might come into contact. However, the team overcame this problem by using an advanced version of cross-linking mass spectrometry, specifically designed for virus-infected cells. This enabled them to capture interactions that occurred briefly or within specific cell regions, while also providing structural information about how these interactions took place.
To enhance the accuracy of the results, the researchers compared their experimental data with computer structural modeling using a modified version of the Nobel Prize-winning AlphaFold algorithm, which allowed them to identify the interacting viral and human proteins and estimate how they align upon contact.
The findings, published in the journal Nature Microbiology, revealed two prominent strategies used by the influenza A virus to take over human cells.
The first strategy revolves around the hemagglutinin protein on the virus's surface, which influenza uses to attach to and enter host cells. Researchers tracked this protein as it traveled through the cell's internal transport and processing network, discovering that several human proteins helped fold and modify hemagglutinin correctly during infection. The functions of some of these host proteins were previously poorly understood.
The second strategy was even more surprising, as the team found that influenza A infection caused the dissolution of subnuclear particles, which are small, droplet-like compartments located inside the cell nucleus. When these particles break down, they release proteins that bind to RNA, which the virus may use to support its replication.
Lead author Iulia Kotova confirms that this event was consistently repeated across every cell line and every influenza strain they tested, suggesting it is not merely a side effect of infection but a deliberate strategy by the virus. This dissolution may have a secondary benefit for the virus, as evidence indicates these particles contribute to cellular stress responses and the regulation of antiviral genes; therefore, disrupting them could also weaken parts of the cell's defense response.
The researchers confirmed the possibility of applying this methodology to other viruses capable of causing a pandemic, such as H5N1, to map their interaction with human cells and develop more effective treatments and vaccines.
