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CRISPR-Cas9 Screening Identifies CDK2 as a Critical Host Factor Enhancing Zika Virus RdRp Activity and Immune Evasion

ABSTRACT: Zika virus (ZIKV) is a global health threat that can cause severe neurological defects, but specific antiviral therapies are lacking. Through a kinase-focused CRISPR-Cas9 screen, we identified cyclin-dependent kinase 2 (CDK2) as an essential host factor for ZIKV infection. We demonstrate that CDK2 directly binds to and phosphorylates the viral RNA polymerase NS5, enhancing its RNA synthesis activity to drive viral replication. In human cells, this phosphorylation also potentiates NS5-mediated degradation of STAT2 and suppression of type I interferon signaling, representing a synergistic immune-evasion mechanism. Pharmacological inhibition of CDK2 with clinical-stage compounds, SNS-032 and Fadraciclib, effectively limited ZIKV replication in human cells, brain organoids, and immunocompromised mice. These inhibitors also restricted Dengue virus replication, indicating that targeting host CDK2 could be a promising strategy against other flaviviruses. Our work unveils CDK2 as a critical host kinase co-opted by ZIKV and establishes its inhibition as a potential host-directed antiviral approach.

ORGANISM(S): Zika Virus

SUBMITTER: Qiangming Sun

PROVIDER: PXD072639 | iProX | Sun Jan 04 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Zika virus (ZIKV) infection continues to pose a significant public health concern due to limited available preventive measures and treatments. ZIKV is unique among flaviviruses in its vertical transmission capacity (i.e., transmission from mother to fetus) yet the underlying mechanisms remain incompletely understood. Here, we show that both African and Asian lineages of ZIKV induce tunneling nanotubes (TNTs) in placental trophoblasts and multiple other mammalian cell types. Amongst investigated flaviviruses, only ZIKV strains trigger TNTs. We show that ZIKV-induced TNTs facilitate transfer of viral particles, proteins, and RNA to neighboring uninfected cells. ZIKV TNT formation is driven exclusively via its non-structural protein 1 (NS1); specifically, the N-terminal region (50 aa) of membrane-bound NS1 is necessary and sufficient for triggering TNT formation in host cells. Using affinity purification-mass spectrometry of cells infected with wild-type NS1 or non-TNT forming NS1 (pNS1deltaTNT) proteins, we found mitochondrial proteins are dominant NS1-interacting partners, consistent with the elevated mitochondrial mass we observed in infected trophoblasts. We demonstrate that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells, both homotypically and heterotypically, and inhibition of mitochondrial respiration reduced viral replication in trophoblast cells. Finally, ZIKV strains lacking TNT capabilities due to mutant NS1 elicited a robust antiviral Interferon lambda 1/2/3 response, indicating ZIKV's TNT-mediated trafficking also allows ZIKV cell-cell transmission that is camouflaged from host defenses. Together, our findings identify a new stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival. Discerning the mechanisms of ZIKV intercellular strategies offers a basis for novel therapeutic developments targeting these interactions to limit its dissemination.

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CRISPR-Cas9 Screening Identifies CDK2 as a Critical Host Factor Enhancing Zika Virus RdRp Activity and Immune Evasion

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