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

Vet Microbiol. 2025 Jan:300:110288. doi: 10.1016/j.vetmic.2024.110288. Epub 2024 Nov 28.

Abstract

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.

Keywords: Genome-wide CRISPR Screen; NDV; Persistent infection.

MeSH terms

  • A549 Cells
  • Animals
  • CRISPR-Cas Systems
  • Chickens / virology
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Humans
  • Interferon Type I* / genetics
  • Interferon Type I* / immunology
  • Interferon Type I* / metabolism
  • Newcastle Disease* / immunology
  • Newcastle Disease* / virology
  • Newcastle disease virus* / genetics
  • Newcastle disease virus* / immunology
  • Newcastle disease virus* / physiology
  • Signal Transduction*
  • Virus Replication

Substances

  • Interferon Type I