Project name: Enhancers of host immune tolerance to bacterial infection discovered using linked computational and experimental approaches II

Description: Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. We used computational transcriptomics and Xenopus laevis embryos to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling led to definition of a 20-gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, were found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF-1 agonist (1,4-DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multi-omics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.Overall design: Using embryos infected with A. hydrophila that are susceptible to infection, embryos were exposed to prophylaxis and/or post-infection treatment regimens of 40uM 1,4-DPCA. In the prophylactic treatment groups, we explored the effects of pretreating the pathogen or the Xenopus embryos separately to assess differential role of the drug on the overall disease tolerance response.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2022-02-09