Pranav Danthi, Indiana University

Claudia Antonika, Pranav Danthi, Indiana University, Bloomington, Indiana, USA

Pathogenesis and Immunity

The reovirus σ3 protein is a multifunctional protein. As part of the viral outer capsid, it confers stability on the particle. During the early stages of infection, σ3 mediates interaction with cellular receptors and temporally regulates virus disassembly. During later stages of infection, σ3 promotes viral translation. σ3 also functions to suppress the antiviral action of the host protein kinase R (PKR) pathway and prevents the formation of stress granules. In this work, we uncover yet another function of σ3. We find that σ3 is both necessary and sufficient to diminish the levels of members of the host inhibitor of kappaB kinase (IKK) complex. We find that this property of σ3 is strain-specific. Whereas σ3 from some reovirus strains promotes IKK loss, σ3 from others do not. IKK function is important for the induction of an interferon (IFN)-based innate immune response and for cell survival. Using engineered viruses, we demonstrate that IKK loss has biological consequences. Strains that induce IKK loss induce a lower level of type I IFN. These strains are also more cytotoxic. We uncover that σ3 from strains that mediate IKK loss interacts with the IKK complex in both σ3-transfected and infected cells. This interaction promotes turnover of the IKK complex members using the ubiquitin-proteasome pathway. Thus, our work uncovers a previously unrecognized role for reovirus σ3 in controlling the host innate immune response. This work could provide a possible explanation for σ3-dependent differences in the pathogenesis of reovirus in a murine model.