Multi-omics characterization of the monkeypox virus infection

Multiple omics analyses of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here we performed in-depth multi-omics analysis of the transcriptome, proteome and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights in the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncovered regulation of the HIPPO and TGF-ß pathways. We identified dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Our extensive dataset highlights signaling events and hotspots that are perturbed by MPXV that extends the current knowledge on poxviruses. We used integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV.