PUBLICATION
Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection
- Authors
- Matty, M.A., Knudsen, D.R., Walton, E.M., Beerman, R.W., Cronan, M.R., Pyle, C.J., Hernandez, R.E., Tobin, D.M.
- ID
- ZDB-PUB-190130-12
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Beerman, Rebecca, Cronan, Mark, Hernandez, Rafael, Matty, Molly, Tobin, David
- Keywords
- host-directed therapies, immunology, infectious disease, inflammation, light sheet microscopy, microbiology, mycobacterium, p2rx7, phenotypic drug screening, zebrafish
- MeSH Terms
-
- Tissue Culture Techniques
- Receptors, Purinergic P2X7/genetics*
- Receptors, Purinergic P2X7/immunology
- Immunity, Innate/drug effects
- Macrophages/drug effects
- Macrophages/immunology
- Macrophages/microbiology
- Clemastine/pharmacology*
- Tuberculosis, Pulmonary/drug therapy
- Tuberculosis, Pulmonary/microbiology
- Calcium/immunology
- Calcium/metabolism
- Mycobacterium marinum/growth & development
- Mycobacterium marinum/immunology
- Mycobacterium marinum/pathogenicity
- Granuloma/drug therapy*
- Granuloma/genetics
- Granuloma/immunology
- Granuloma/microbiology
- Humans
- Host-Pathogen Interactions/genetics
- Host-Pathogen Interactions/immunology
- Zebrafish/genetics
- Zebrafish/immunology
- Zebrafish/microbiology
- Mycobacterium Infections, Nontuberculous/drug therapy*
- Mycobacterium Infections, Nontuberculous/genetics
- Mycobacterium Infections, Nontuberculous/immunology
- Mycobacterium Infections, Nontuberculous/microbiology
- Drug Repositioning
- Antitubercular Agents/pharmacology*
- Zebrafish Proteins/agonists
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/immunology
- Mycobacterium tuberculosis/pathogenicity
- Larva/drug effects
- Larva/genetics
- Larva/immunology
- Larva/microbiology
- Signal Transduction
- Inflammasomes
- Animals
- Disease Models, Animal
- Anti-Allergic Agents/pharmacology
- Gene Expression Regulation
- PubMed
- 30693866 Full text @ Elife
Citation
Matty, M.A., Knudsen, D.R., Walton, E.M., Beerman, R.W., Cronan, M.R., Pyle, C.J., Hernandez, R.E., Tobin, D.M. (2019) Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection. eLIFE. 8:.
Abstract
Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by multi-drug-resistant strains. Host-directed therapies have been proposed as an orthogonal approach, but few have moved into clinical trials. Here, we use the zebrafish-Mycobacterium marinum infection model as a whole-animal screening platform to identify FDA-approved, host-directed compounds. We identify multiple compounds that modulate host immunity to limit mycobacterial disease, including the inexpensive, safe, and widely used drug clemastine. We find that clemastine alters macrophage calcium transients through potentiation of the purinergic receptor P2RX7. Host-directed drug activity in zebrafish larvae depends on both P2RX7 and inflammasome signaling. Thus, targeted activation of a P2RX7 axis provides a novel strategy for enhanced control of mycobacterial infections. Using a novel explant model, we find that clemastine is also effective within the complex granulomas that are the hallmark of mycobacterial infection.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping