The system: The Danthi laboratory uses mammalian reovirus as the experimental system to dissect events at the virus-host interface. Like its medically and economically important relatives - rotavirus and bluetongue virus - reovirus forms nonenveloped particles that contain a segmented dsRNA genome encapsidated within concentric protein shells. This experimental model is highly amenable to investigation due to the existence of well-characterized biochemical and cell biological reagents and assays, a wealth of structural information about reovirus particles and proteins, and the recent development of a tractable reverse-genetic system to manipulate the reovirus genome. Our laboratory employs mammalian reovirus as an experimental tool to study virus entry into host cells and virus-induced cell death.

Virus entry: The reovirus genome is surrounded by two concentric protein shells. Successful initiation of infection by reovirus requires delivery of the genome-containing reovirus inner shell (or core) across the host cell membrane. This process occurs via a series of biochemical and structural changes to the reovirus particle. Much remains unknown about the host and viral determinants that control these changes that allow transport of a large (~ 70 nm) macromolecular cargo across the host membrane. We use a combination of genetic, biochemical and biophysical approaches to understand these questions. Because the overall strategy for entering cells used by other nonenveloped viruses is similar, our studies will uncover conserved mechanisms by which phylogenetically distinct viruses initiate infection. 

Virus-induced cell death:Cell death induced as a consequence of virus infection is a determinant of viral pathogenesis. Depending on cell type, infection of host cells by reovirus results in the induction of two distinct forms of regulated cell death – apoptosis and necrosis. Interestingly, though events in cell entry are sufficient for apoptosis induction, viral genome replication is required for necrosis induction. We are interested in understanding how innate immune detection of viral components interfaces with the prodeath signaling cascade. This work connects innate immune detection of reovirus infection with . In addition to highlighting how virus infection results in host cell death, these studies will enhance an understanding of the regulation of host survival and death pathways. Because wild-type reovirus is in clinical trials as an anticancer therapeutic, these studies also may help develop a more efficacious oncolytic vector.