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Multilevel proteomics reveals common and specific host perturbations by Monkeypox and Vaccinia viruses (full proteome)

ABSTRACT: The global spread of Monkeypox virus (MPXV) has resulted in the urgent need for an in-depth molecular characterization of the virus infection. Multiple omics studies on Vaccinia virus have extended our knowledge of poxvirus pathophysiology (REFs). Nevertheless, there are no comparative studies that would include an in-depth comparison of MPXV with other poxviruses in the context of molecular biology. Here, we report a comparative time-resolved proteomic study of MPXV and vaccinia viruses and a concurrent multi-omics study of MPXV infection in primary human cells. Using state-of-the-art proteomics, we profiled the virus-host interplay on the transcriptome, proteome and phosphoproteome levels in primary human foreskin fibroblasts. Pathway analysis in combination with projecting the gathered data onto the global network of host-signaling interactions revealed crosstalk between the perturbations at different levels, enabling identification of distinct and common molecular mechanisms of poxviruses. The NF-κB pathway, a signaling pathway governing immunomodulation and inflammation, was unexpectedly activated by MPXV but not VacV, while MPXV exhibited an astounding resistance to the effects of antiviral interferon response, potentially explaining the unique pathogenicity hallmarks of the monkeypox. Our extensive dataset highlights many signaling events and hotspots that influence the MPXV life cycle and may be used to guide rational design of both virus- and host-directed therapies, which we exemplify by identifying inhibitors of XXX, YYY, and ZZZ with potent antiviral efficacy against MPXV and/or VacV.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Orthopoxvirus Monkeypox Virus

TISSUE(S): Primary Cell, Fibroblast

SUBMITTER: Quirin Emslander

LAB HEAD: Andreas Pichlmair

PROVIDER: PXD040811 | Pride | 2024-07-25

REPOSITORIES: Pride

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			Action	DRS
	Ecl1_0083_R0065-01_S001177_L_H01_LFQ.raw	Raw
	Ecl1_0083_R0065-01_S001177_L_H02_LFQ.raw	Raw
	Ecl1_0083_R0065-01_S001177_L_H03_LFQ.raw	Raw
	Ecl1_0083_R0065-01_S001177_L_H04_LFQ.raw	Raw
	Ecl1_0083_R0065-01_S001177_L_H05_LFQ.raw	Raw

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Project description:Three experiments, corresponding to the three figures in the article, are represented in this set. Each experiment was an ex vivo treatment time course as described in the paper. For each of the experiments, mRNA was isolated at the indicated time points, cDNA was directly prepared by reverse transcription in the presence of Cy5-labeled dUTP, and the expression profiled using Cy3-labeled cDNA prepared by reverse transcription of Stratagene Universal Human Reference RNA as a control. One experiment, corresponding to Figure 1 in the paper, is a set of infection, or mock-infection time courses, in which each of three cell types: primary human dermal fibroblasts, primary human macrophages, or HELA cells were respectively infected with Monkeypox virus, Vaccinia virus, or Ebola virus, or mock-infected. Infected cells or mock-infected cells were harvested and lysed at the indicated times after infection and mRNA isolated for analysis following the protocol described above. The second experiment, corresponding to Figure 2 in the paper, is a set of treatments of human dermal fibroblasts, each in 24-well plates with either: PBS only (mock), interferon alpha (IFN-alpha) at 0.6 pM final concentration (Sigma, St. Louis, MO), tumor necrosis factor alpha (TNF-alpha) at 0.6 pM final concentration (Sigma), PMA at 25ng/mL final concentration plus ionomycin at 1micromolar final concentration, polyinosinic-polycytidylic acid as potassium salt (poly(I-C)) at 100 microg/mL final concentration (Sigma), Escherichia coli 055:B5 lipopolysaccharide (LPS) at 1microg/mL final concentration (Sigma), or dexamethasone at 1 micromolar final concentration (Sigma). Cells were harvested and lysed at the indicated times and mRNA isolated for analysis following the protocol described above. The third experiment, corresponding to Figure 3 in the paper, is a set of infections or mock-infections of human dermal fibroblasts, or human primary macrophages, with Monkeypox virus or Vaccinia virus, respectively, followed by treatment with either ionomycin + phorbol myristic acid (PMA) or with poly(I-C). The intention of the experiment was to investigate whether prior infection altered the response of the cells to the chemical agents. Cells were harvested and lysed at the indicated times and mRNA isolated for analysis following the protocol described above. Description of sample characteristics: Time: Time after infection or Mock infection Infection: Ebola-Zaire/killed Monkeypox Virus/Mock infection/Monkaypox Virus/None/Pre infection/Vaccinia NY/Vaccinia WR Compound Based Treatment: Dexamethasone/Interferon-alpha/Ionomycin + PMA/LPS/PBS/polyinosinic-polycytidylic acid/TNF-alpha Cell Type: Primary Human Dermal Fibroblast/Primary Human Macrophage/HeLa Figure in article: Numbers group slides that are represented in the same figure of the article. A stimulus or stress experiment design type is where that tests response of an organism(s) to stress/stimulus. e.g. osmotic stress, behavioral treatment

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Multilevel proteomics reveals common and specific host perturbations by Monkeypox and Vaccinia viruses (full proteome)

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