Abstract

Tick-borne encephalitis virus (TBEV) poses an increasingly significant threat to public health. Here, we delved into the virus-host interactome and discovered that TBEV has a profound impact on multiple host cellular pathways. Viral pre-membrane protein (prM), non-structural proteins NS1, NS2B3, NS4A, and NS5 remodel the host’s innate immune responses. PrM and NS2B3 are involved in autophagy, NS4A is associated with neurodegenerative diseases, and NS5 participates in spliceosome dynamics, ribosomal biogenesis, cell cycle regulation, and DNA damage response. Notably, TBEV infection causes G0/G1 cell cycle arrest in host cells. NS5 interacts with histone acetyltransferase P300 to upregulate P16 expression, suppressing CDK4 and resulting in cell cycle arrest. Elevated P16 and reduced CDK4 levels were observed in TBEV-infected brain organoids. The P300 inhibitors and CDK4 agonist can reverse virus-induced cell cycle arrest and inhibit viral replication. Further analysis uncovered potential antiviral targets like KAT6A, XIAP, and RIOK1/BRD9. These findings provide valuable insights into TBEV pathogenicity and hold promise for antiviral drug development.