In a groundbreaking study, Northwestern Medicine researchers have unveiled the astonishing tactics employed by poxvirus to commandeer the host’s protein production system, paving the way for its own replication and spread.

Poxviruses, infamous for causing deadly diseases like smallpox, exhibit a remarkable dependency on the host's ribosomes—the very machinery that synthesizes proteins—to convert their viral mRNA into functional proteins. Yet, the intricate methods they use to infiltrate and exploit these cellular factories have remained largely unexplored until now.

Derek Walsh, PhD, a leading microbiologist and senior author of the study, expressed intrigue over this phenomenon, stating, "Despite being a highly autonomous DNA virus in many ways, poxviruses still rely on access to host ribosomes to survive."

Utilizing cutting-edge RNA sequencing and polysome profiling techniques, the team uncovered a complex interaction between viral and host mRNAs during infection. Walsh noted that, as the virus progresses and induces a condition known as host shutoff—essentially sidelining the host’s own mRNA in favor of its own—some host mRNAs still manage to be translated, albeit through an unusual initiation process.

Employing advanced cryo-electron microscopy in collaboration with the University of Utah, researchers observed striking alterations in the infected cells, including structural movements in the ribosomal 40S head domain during the translation initiation phase.

The study highlighted the virus's reliance on specific cellular proteins, namely the ribosomal protein Receptor for Activated C Kinase 1 (RACK1) and eukaryotic Initiation Factor eIF3, in orchestrating its own protein synthesis while effectively curtailing host defenses.

These pivotal discoveries shed light on the sophisticated ways in which viruses can reprogram cellular functions to prioritize their own needs, sparking hope for new antiviral strategies aimed at sabotaging these processes.

Walsh emphasized the complexity of poxvirus interactions with ribosomes, stating, "This research reveals the nuanced ways poxviruses manipulate ribosomal function and the intricate dance of host and viral translation as infection progresses." He is committed to continuing his investigation into RACK1 and the roles of additional ribosomal proteins involved in virus replication.

The study was led by Chorong Park, PhD, a dedicated postdoctoral fellow in Walsh's lab and was generously supported by the National Institutes of Health.