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The translational landscape of virally infected cells

Final Report Summary - HOST TRANSLATION (The translational landscape of virally infected cells)

As obligate intracellular parasites, virus reproduction requires host cell functions. Despite substantial variation in genome size, nucleic acid composition, and their repertoire of encoded functions, all viruses remain unconditionally dependent upon the protein synthetic machinery resident within their cellular hosts to translate viral mRNAs. Access to the translation apparatus, however, is patrolled by powerful host immune defenses programmed to restrict viral invaders. In my lab we study the tactics and mechanisms used by viruses to appropriate control over host ribosomes, subvert host defenses and dominate the infected cell translational landscape. Our research in the using the CIG support focused on two major pathogens; a small RNA virus, Influenza A (IAV) and a large DNA virus, Human cytomegalovirus (HCMV).
Host shutoff is a common strategy used by many viruses to repress cellular mRNA translation, allowing efficient translation of viral mRNAs. In our work we used e RNA-seq, ribosome profiling and single molecule FISH to accurately quantify IAV induced host shutoff at both RNA and translation levels (Bercovich-Kinori et al. 2016). We reveal that IAV shutoff is mediated solely by interfering with cellular mRNA levels and we uncover that transcripts, coding for cell maintenance processes such as oxidative phosphorylation, were refractory to IAV shut-off affects. We show that shorter and more structured transcripts (transcripts with higher GC content) tend to be less effected by IAV infection.
We further demonstrate that indeed continuous oxidative phosphorylation activity is important for IAV propagation. Our results thus challenge the notion of host shut-off being a blunt, indiscriminate instrument to halt host gene expression and reveal that shutoff could be selective, allowing maintenance of important housekeeping functions in infected cells. More broadly, this work lays the technological foundation for exploring host shutoff mechanisms during infection
A different tactic was observed in HCMV-infected cells, where host protein synthesis is not globally suppressed so it was assumed that host protein synthesis proceeded uninterrupted. Using ribosome profiling and RNA-seq we showed that HCMV dramatically re-shape the infected cell translation landscape. This translational reprogramming was dependent upon virally induced mTOR activation. Importantly, we show that interfering with the virus-induced activation of cellular mRNA translation can limit or enhance HCMV growth (Tirosh et al. 2015).
Our work, thus, illustrate how genome-wide methodologies advance the understanding of how viruses facilitate selective translation of host mRNAs needed for their propagation.