Cells are hard-wired to detect viral pathogens and rapidly respond with a web of antiviral defense. Virus detection leads to type I interferon (IFN) production and signaling, ultimately resulting in transcription of hundreds of IFN-stimulated genes (ISGs). Collectively, ISGs establish a strikingly potent antiviral state; however, viruses have evolved ways to antagonize IFN production and signaling shortly after infection. The host's need for speed in responding to infection is therefore paramount. We hypothesize that an important and understudied mechanism that cells use to rapidly respond to infection prior to the production of ISGs is by altering their cellular translatome-in other words, by rapidly altering the translation of pre-existing mRNAs to facilitate a robust antiviral response. We propose to fill this knowledge gap by using two powerful techniques to measure translation efficiency and nascent protein synthesis: ribosome profiling and mass spectrometry. Further, we will continue characterizing two ISGs, MOV10 and ADAR1, that were identified in our previous ISG screens. Our results indicate that both ISGs are likely to impact mRNA translation during the innate immune response. These studies will broaden and deepen our knowledge of the antiviral response in novel ways.
Virus infections have an enormous negative impact on economies, agriculture, and importantly, on human health. Unfortunately, broadly acting antiviral therapies do not yet exist. Here we propose to improve our fundamental understanding of the evolutionarily tried-and-true host antiviral response in the hope that this knowledge will lead to the development of broad-spectrum antiviral drugs.
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