Poxviruses are a family of DNA viruses that have afflicted humans throughout history. Notably, smallpox devastated the human population by killing more people than any other disease. Despite being eradicated, the threat of emerging poxviruses is still a reality. New human poxviruses are still being discovered and evolving zoonotic infections like African monkeypox have experts concerned it is only matter of time before a new smallpox-like disease emerges. In fact, there is an ongoing monkeypox outbreak in Nigeria as of September 2017. Although live smallpox vaccines can protect against other poxviruses, they are too dangerous for pregnant women, those with eczema, and the immunocompromised, leaving large portions of the population unprotected. Poxviruses are also used as oncolytics and gene therapy vectors, while in basic research they been invaluable tools that uncovered important biological processes such as mRNA capping and polyadenylation. Therefore, research into poxviruses continues to be significant for both clinical and basic research. Poxviruses are incredibly self-sufficient and encode almost everything they need to replicate. Despite this, poxviruses still rely on host ribosomes to translate viral mRNAs and have evolved strategies to hijack them. Recent evidence suggests that ribosomes have the capacity to be ?specialized? to selectively translate mRNAs. What dictates this ?specialization? is largely unknown, but evidence suggests that changes to the subunit composition and/or post-translational modifications (PTMs) to ribosomal subunit proteins plays a key role. It was recently uncovered that following activation of ribosome quality control (RQC), two factors, ZNF598 and RACK1, induce PTMs on the ribosomal complex. Our lab recently discovered that poxviruses uniquely modify RACK1 to selectively enhance translation of viral mRNAs. Curiously, preliminary data shows ZNF598 is also required for infection suggesting a link between RQC pathways and infection. Therefore, we hypothesize poxviruses usurp RQC factors by inducing PTMs to ?specialize? the ribosome to selectively enhance translation of viral mRNAs. We devised two specific aims that focus on determining what roles ZNF598 and RACK1 play during infection. Knowledge gained would not only further our understanding of poxvirus biology, but would also provide valuable insights into the RQC pathway and identify novel therapeutic targets to treat poxvirus-related diseases.
Poxviruses are emerging and zoonotic viruses that infect humans and cause severe disease. The current live smallpox vaccine is too dangerous for use in a large portion of the population including pregnant women, children, immunocompromised patients, and people suffering from skin conditions such as eczema. The goal of this project is identify highly specialized host factors necessary for viral infections that may reveal novel therapeutic targets that can be used to suppress poxvirus infection.
