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Monkeypox virus (MPXV) is comprised of two clades: Congo Basin MPXV, with an associated case fatality rate of 10%, and Western African MPXV, which is associated with less severe infection and minimal lethality. We thus postulated that Congo Basin and West African MPXV would differentially modulate host cell responses and, as many host responses are regulated through phosphorylation independent of transcription or translation, we employed systems kinomics with peptide arrays to investigate these functional host responses. Using this approach we have demonstrated that Congo Basin MPXV infection selectively down-regulates host responses as compared with West African MPXV, including growth factor- and apoptosis-related responses. These results were confirmed using fluorescence-activated cell sorting analysis demonstrating that West African MPXV infection resulted in a significant increase in apoptosis in human monocytes as compared with Congo Basin MPXV. Further, differentially phosphorylated kinases were identified through comparison of our MPXV data sets and validated as potential targets for pharmacological inhibition of Congo Basin MPXV infection, including increased Akt S473 phosphorylation and decreased p53 S15 phosphorylation. Inhibition of Akt S473 phosphorylation resulted in a significant decrease in Congo Basin MPXV virus yield (261-fold) but did not affect West African MPXV. In addition, treatment with staurosporine, an apoptosis activator resulted in a 49-fold greater decrease in Congo Basin MPXV yields as compared with West African MPXV. Thus, using a systems kinomics approach, our investigation demonstrates that West African and Congo Basin MPXV differentially modulate host cell responses and has identified potential host targets of therapeutic interest.
Pubmed ID: 22205724
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Publicly available database of the genes, proteins, experimentally-verified interactions and signaling pathways involved in the innate immune response of humans, mice and bovines to microbial infection. The database captures coverage of the innate immunity interactome by integrating known interactions and pathways from major public databases together with manually-curated data into a centralized resource. The database can be mined as a knowledgebase or used with the integrated bioinformatics and visualization tools for the systems level analysis of the innate immune response. Although InnateDB curation focuses on innate immunity-relevant interactions and pathways, it also incorporates detailed annotation on the entire human, mouse and bovine interactomes by integrating data (178,000+ interactions & 3,900+ pathways) from several of the major public interaction and pathway databases. InnateDB also has integrated human, mouse and bovine orthology predictions generated using Ortholgue software. Ortholgue uses a phylogenetic distance-based method to identify possible paralogs in high-throughput orthology predictions. Integrated human and mouse conserved gene order and synteny information has also been determined to provide further support for orthology predictions. InnateDB Capabilities: * View statistics for manually-curated innate immunity relevant molecular interactions. New manually curated interactions are submitted weekly. * Search for genes and proteins of interest. * Search for experimentally-verified molecular interactions by gene/protein name, interaction type, cell type, etc. * Search genes/interactions belonging to 3,900 pathways. * Visualize interactions using an intuitive subcellular localization-based layout in Cerebral. * Upload your own list of genes along with associated gene expression data (from up to 10 experimental conditions) to interactively analyze this data in a molecular interaction network context. Once you have uploaded your data, you will be able to interactively visualize interaction networks with expression data overlaid; carry out Pathway, Gene Ontology and Transcription Factor Binding Site over-representation analyses; construct orthologous interaction networks in other species; and much more. * Access curated interaction data via a dedicated PSICQUIC webservice.
View all literature mentionsCell line BS-C-1 is a Spontaneously immortalized cell line with a species of origin Chlorocebus pygerythrus (Vervet monkey)
View all literature mentionsCell line Vero C1008 is a Spontaneously immortalized cell line with a species of origin Chlorocebus sabaeus
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