Genome-wide CRISPR screen reveals specific role of type I interferon signaling pathway in Newcastle disease virus establishment of persistent infection

Newcastle disease virus (NDV) is a potent oncolytic agent that exhibits sensitivity to a wide range of Cancer cells. Unfortunately, some Cancer cells are able to resist NDV-mediated oncolysis, by developing a persistent Infection. The mechanism of persistency of Infection remains poorly understood. In this study, a genome-wide CRISPR screen was conducted on Non-Small Cell Lung Cancer cells (A549) to identify key host factors for NDV Infection. Interestingly, a persistent Infection was established in the surviving cells. CRISPR high-throughput screening results showed that members of the type I interferon signaling pathway (JAK1, STAT1, STAT2 and IRF9) were identified as top hits in the surviving cells. Further studies found that the type I IFN signaling pathway is intact in A549 cells, and a violent cytokine storm was induced after NDV Infection. Both NDV Infection and cytokine storm can induce cell death in A549 cells. We further blocked the type I interferon signaling pathway, and impaired type I interferon signaling pathway promoted NDV replication, but it did attenuate cell death induced by cytokine storm. Furthermore, persistent Infection is more easily established in type I interferon signaling pathway-impaired A549 cells than in wild-type A549 cells. These findings suggest that the type I interferon signaling pathway plays a decisive role in persistent Infection by regulating the Antiviral immunity and cytokine storm inducing cell death.