Reovirus Z-RNAs activate ZBP1 dependent cell death

Reovirus (ReoV) is an enteric dsRNA virus which can infect a wide range of mammals and induce intestinal and autoimmune diseases due to the cell death elicited during infection. The mechanisms by which ReoV induces such cell death are unclear. For decades, ReoV was thought to cause mainly apoptosis in infected cells. Recent studies have shown that ReoV can also activate necroptosis, a caspase-independent form of inflammatory programmed cell death reliant on the kinase RIPK3 and its substrate MLKL. The mechanisms by which both necroptosis and apoptosis are activated during ReoV infection, and the importance of these cell death pathways to ReoV pathogenesis, are largely unknown. Here, we show that Z-DNA Binding Protein 1 (ZBP1) initiates both apoptosis and necroptosis during ReoV infections. We have also discovered that ReoV generates Z-RNA, the left-handed conformation of double-helical (ds)RNA, which are sensed by ZBP1 in the cytoplasm of infected cells. These ReoV Z-RNAs originate primarily from the positive-sense viral RNAs, which fold-back to produce dsRNA. ZBP1 then initiates RIPK3-driven pathways of apoptosis and necroptosis, as well as RIPK3- independent apoptosis driven by RIPK1. In vivo, ZBP1 is essential for limiting virus dissemination to cardiac tissues following oral and intracranial infection, and for preventing lethality in mice. These results demonstrate that ZBP1-driven Z-RNA sensing and cell death play an integral role in controlling ReoV infection.