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Viruses are completely reliant on hijacking a host cell’s protein synthesis machinery for their own propagation, and overcoming the anti-viral defence mechanisms that cells have evolved. When viruses succeed, the host cell produces viral proteins instead of host proteins, a process known as host shutoff, and the spread of infection accelerates.
The EU-funded HOST TRANSLATION project investigated the tactics and mechanisms used by viruses to both take control of a host cell’s ribosomes — where the translation stage of protein synthesis occurs — and to subvert host cell defences.
‘Our research focused on two major pathogens: a small RNA virus, influenza A, the causal agent of flu, and a large DNA virus, human cytomegalovirus (HCMV), which is an abundant virus that can lead to a severe congenital disease, as well as morbidity and mortality in immunocompromised adults,’ says Noam Stern-Ginossar, of the Weizmann Institute of Science in Israel.
For both these viruses, the means by which infection changes the translation of host genes into proteins is still poorly defined. The project team used innovative methods to study how these viruses ‘dominate the infected cell’s translational landscape’. These new methods and the insights they provide can help in the development of new anti-viral treatments.
Cellular takeover
Viruses use two main strategies to co-opt the cell’s translation machinery: either host mRNAs are destroyed, or the machines that read mRNA molecules are manipulated to read only the viral instructions.
It appears that most viruses dedicate themselves to just one of these strategies. However, the evidence suggests that influenza A can use both strategies to induce host shutoff. The project team studied the influenza A virus in infected human lung cells and found that it primarily reduces the amount of host mRNA in the cells.
The results challenge the notion that host shutoff is necessarily a blunt, indiscriminate instrument. The team found that it could be more selective than previously thought, allowing maintenance of important housekeeping functions in infected cells.
In contrast, the project team showed that HCMV dramatically re-shaped the infected cell’s translation landscape. An important result was showing that interference with the virus-induced activation of cellular mRNA translation can limit HCMV growth.
Targeting flu
‘We used a recently developed powerful tool that allows us to determine the quantity of any protein produced by a living cell. As proteins are the building blocks of most of the biological processes within the cell, the use of this new high-throughput technique provides novel resolution,’ Stern-Ginossar says.
This approach uses a novel deep-sequencing technique, called ribosome profiling, to provide a comprehensive view of translation events. It therefore enables a determination of the identity and the relative levels of translation of each protein during the course of infection.
By applying the project’s innovative technique to virally infected cells at different time points, the project team could plot the course of infection and precisely map how the viruses co-opt the cell’s machinery to make viral proteins.
This provides valuable new information about the translational control strategies used by these viruses to re-programme the host’s cellular machinery, which could help in the development of new approaches to combating the spread of pathogenic viruses.
‘A future challenge is to find out exactly how the influenza A virus distinguishes between different cellular mRNAs,’ says Stern-Ginossar. ‘If we identify the viral proteins which control this specific process, this knowledge may help to develop new treatments for flu.’
HOST TRANSLATION received funding through the EU’s Marie Skłodowska-Curie Actions programme.