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Significance Human cytomegalovirus (HCMV) is a β-herpesvirus that establishes life-long infection, leaving the risk of persistent reactivation and disease. Inhibition of viral entry into susceptible cells is an attractive strategy to prevent infection. MCMV is a surrogate to model host-pathogen interactions; however, the precise mechanism of MCMV entry remains incomplete. Here, we utilized a pronecroptotic form of MCMV as a strategy to perform a genome-wide forward genetic screen to identify host factors essential for infection. We characterize VEGF receptor Nrp-1 as a novel mediator of MCMV infection required for viral gene expression, replication, and necroptosis induction. Our observations define Nrp-1 as a key cellular factor that facilitates MCMV infection and may be an entry receptor for the virus.

Necroptosis-based CRISPR knockout screen reveals Neuropilin-1 as a critical host factor for early stages of murine cytomegalovirus infection