Antiviral Mechanisms of the Yeast RNA Decay Machinery And Viral Countermeasures

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Intellectual Merit: Host cells have developed a variety of methods to detect viral infection and reduce viral load. The adaptive immune system that generates antibodies against viruses is a well-characterized part of the antiviral defense, but this defense mechanism is only active in jawed-vertebrates. A second branch of the immune system, called the innate immune system, can also battle virus infection. The innate immune system is found in many different eukaryotic species and has been studied in vertebrates, invertebrates and plants, but remains relatively poorly studied in fungi. This project will focus on studying the mechanisms that cells use to combat viruses and the tactics that viruses, in return, use to evade host defenses. A key challenge in the host defense is to distinguish normal cellular RNAs from RNAs encoded by viral invaders. Host messenger RNA generally contains a single strand of RNA that is modified at its 5' start with a cap structure and at its 3' end with a poly(A) tail. RNA from viruses may be double stranded, uncapped, and/or lack a poly(A) tail. Several branches of the innate immune system recognize these general features of viral RNA. This research aims to demonstrate through the use of Baker's yeast and Yeast killer viruses that eukaryotic cells have an additional type of innate immunity against viral infection. Yeast contains Ski proteins, which function in RNA decay, and have an antiviral function. The hypothesis is that the yeast Ski proteins recognize RNA that lacks a poly(A) tail, such as viral RNA, and target it for degradation. It has been shown that the L-A virus has a process to produce uncapped cellular mRNA, and the mechanism by which this aids virus replication will also be investigated. The research will provide new insights into the mechanisms by which viruses evade the host innate immune system. Broader Impacts: The research includes significant educational opportunities for graduate and undergraduate students. The research will be carried out in a lab with an established track record of giving undergraduate students an opportunity to do basic biological research. Undergraduate students who have worked in the lab for a summer are now in top-tier graduate schools. This research uses yeast genetic methods, which are especially well suited to teach students the process of generating a hypothesis, designing experiments to test this hypothesis and interpreting the resulting data within a summer research program. Contacts with three local minority-serving universities have been established to help recruit undergraduate students to participate in the proposed research.