Related Experiment Video
Updated: Sep 8, 2025
Experimental Infection with Listeria monocytogenes as a Model for Studying Host Interferon-γ Responses
Published on: November 16, 2016
Enhancers of Host Immune Tolerance to Bacterial Infection Discovered Using Linked Computational and Experimental
Megan M Sperry1,2, Richard Novak1, Vishal Keshari1
1Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, 02115, USA.
Abstract:
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. Computational transcriptomics and Xenopus laevis embryos are used 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 leads 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, are found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF-1α 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 multiomics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.
Insights
This study explores host tolerance as an alternative to antibiotics for bacterial infections. Researchers identified conserved pathways and drugs that enhance host survival against pathogens.
Area of Science:
- Infectious Diseases
- Immunology
- Computational Biology
Background:
- Antibiotics reduce pathogen load but do not address host susceptibility.
- Host tolerance offers an alternative therapeutic strategy by enhancing resilience to infection.
- Xenopus laevis embryos serve as a model to study conserved infection responses.
Purpose of the Study:
- Discover infection response pathways using computational transcriptomics.
- Identify potential drugs that induce broad host tolerance to bacterial pathogens.
- Validate the efficacy of identified drugs in a Xenopus embryo model.
Main Methods:
- Utilized computational transcriptomics to analyze gene expression in Xenopus embryos.
- Defined a 20-gene signature to differentiate tolerant and susceptible infection states.
- Employed Xenopus embryo infection model with various bacterial species (A. baumannii, K. pneumoniae, S. aureus, S. pneumoniae, A. hydrophila, P. aeruginosa).
Main Results:
- Xenopus showed natural tolerance to certain bacteria but susceptibility to others (A. hydrophila, P. aeruginosa).
- Identified conserved gene pathways involved in host tolerance, including metal ion binding and hypoxia.
- Administering deferoxamine (metal chelator) or 1,4-DPCA (HIF-1α agonist) improved survival in embryos infected with lethal A. hydrophila.
Conclusions:
- Host tolerance is a viable alternative therapeutic strategy for bacterial infections.
- Xenopus embryo model combined with multiomics is effective for discovering infection mechanisms and repurposing drugs.
- Conserved pathways suggest potential for developing broad-acting tolerance-inducing therapies in mammals.
Related Concept Videos
01:20Special Features of Adaptive Immunity
The primary cell types involved in adaptive immunity are T cells and B cells. Each type has a unique role in defending the body against pathogens. T cells are responsible for cell-mediated immunity. They identify and eliminate infected cells directly,...
01:16Transduction
01:40Cell-mediated Immune Responses
01:31Defense Against Bacterial Pathogens
Phagocytes
Phagocytes are the frontline soldiers of the immune system. They include neutrophils and macrophages. Neutrophils are the most abundant type of white blood cell and are quickly mobilized to the site of infection. Macrophages are larger cells that patrol...