Multi-omics characterization of the monkeypox virus infection

• Published in: Nature communications Vol. 15; no. 1; pp. 6778 - 19
• Main Authors: Huang, Yiqi, Bergant, Valter, Grass, Vincent, Emslander, Quirin, Hamad, M. Sabri, Hubel, Philipp, Mergner, Julia, Piras, Antonio, Krey, Karsten, Henrici, Alexander, Öllinger, Rupert, Tesfamariam, Yonas M., Dalla Rosa, Ilaria, Bunse, Till, Sutter, Gerd, Ebert, Gregor, Schmidt, Florian I., Way, Michael, Rad, Roland, Bowie, Andrew G., Protzer, Ulrike, Pichlmair, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/31; 140/58; 38/1; 38/39; 38/77; 38/90; 38/91; 631/326/596/1746; 631/45/475; 631/80/458/1733; 631/80/86; Antiviral Agents - pharmacology; Biological analysis; Fibroblasts - metabolism; Fibroblasts - virology; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Infections; Kinases; Monkeypox; Monkeypox virus - genetics; Mpox (monkeypox) - metabolism; Mpox (monkeypox) - virology; multidisciplinary; Multiomics; Phosphorylation; Proteins; Proteome - metabolism; Proteomes; Proteomics - methods; Science; Science (multidisciplinary); Signal Transduction; Splicing factors; Target recognition; Therapeutic targets; TOR protein; Transcriptome; Transcriptomes; Transforming growth factor-b; Viral Proteins - genetics; Viral Proteins - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51074-6

Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-β pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use 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. Multi-omics profiling of monkeypox virus infected human primary cells was used to characterize the infection process and to prioritize potential antiviral drug targets.