Uncovering How Poxvirus Hijacks Host Proteins to Spread

Northwestern Medicine scientists have uncovered new details about how poxvirus hijacks its host’s protein synthesis machinery to multiply and spread, according to a study published in Nature Microbiology.

Poxviruses, including deadly diseases like smallpox, depend on host ribosomes—the cellular machinery responsible for protein production—to translate their viral mRNA into proteins. Exactly how poxviruses hijack their host’s ribosomes, however, has not been well understood, said Derek Walsh, PhD, professor of Microbiology-Immunology, who was senior author of the study.

“What fascinates us is that all viruses are dependent on gaining access to host ribosomes, even poxviruses, which are highly unusual DNA viruses that are so self-sufficient in other processes,” Walsh said.

In the study, Walsh and his collaborators analyzed infected cells using RNA sequencing and polysome profiling. They found a complex interplay between viral and host mRNAs during infection, Walsh said.

“We found that at later times of infection, when the virus causes a phenomenon called host shutoff to favor viral mRNA translation, some host mRNAs continue to be translated, but they use a different, non-canonical mode of initiation to that of viral mRNAs,” Walsh said.

Using advanced cryo-electron microscopy together with their collaborators at the University of Utah, the investigators then visualized significant changes in infected cells. 

“We found that poxvirus infection causes structural changes to how the 40S head domain moves during initiation,” Walsh said.

They also observed that the virus relies on specific cellular machinery to facilitate its own protein synthesis: the small ribosomal protein Receptor for Activated C Kinase 1 (RACK1) and the eukaryotic Initiation Factor eIF3. 

The findings provide new insight into how viruses can rewire cellular machinery, ensuring the production of key viral proteins while suppressing host defenses. Understanding these strategies could open new avenues for developing antiviral treatments by disrupting this process, Walsh said.

“This really starts to get into the nuance of how poxviruses modify ribosome function and the complexity of host and viral translation during later times of infection,” Walsh said. “It also offers a great example of how ribosome function can be modified in general.”

Moving forward, Walsh and his laboratory will continue to investigate the role of RACK1and the roles of additional proteins involved in viral replication.

“While we continue to try to understand what RACK1is doing to control translation during infection, we also have 79 other ribosomal proteins left to figure out.” he said.

Chorong Park, PhD, a postdoctoral fellow in the Walsh laboratory, was first author of the paper.

The study was supported by funding from the National Institutes of Health under grants R35GM133772, R01AI127456 and R01AI179744.