ZFIN ID: ZDB-PUB-190130-12
Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection
Matty, M.A., Knudsen, D.R., Walton, E.M., Beerman, R.W., Cronan, M.R., Pyle, C.J., Hernandez, R.E., Tobin, D.M.
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:
  • Animals
  • Anti-Allergic Agents/pharmacology
  • Antitubercular Agents/pharmacology*
  • Calcium/immunology
  • Calcium/metabolism
  • Clemastine/pharmacology*
  • Disease Models, Animal
  • Drug Repositioning
  • Gene Expression Regulation
  • Granuloma/drug therapy*
  • Granuloma/genetics
  • Granuloma/immunology
  • Granuloma/microbiology
  • Host-Pathogen Interactions/genetics
  • Host-Pathogen Interactions/immunology
  • Humans
  • Immunity, Innate/drug effects
  • Inflammasomes
  • Larva/drug effects
  • Larva/genetics
  • Larva/immunology
  • Larva/microbiology
  • Macrophages/drug effects
  • Macrophages/immunology
  • Macrophages/microbiology
  • Mycobacterium Infections, Nontuberculous/drug therapy*
  • Mycobacterium Infections, Nontuberculous/genetics
  • Mycobacterium Infections, Nontuberculous/immunology
  • Mycobacterium Infections, Nontuberculous/microbiology
  • Mycobacterium marinum/growth & development
  • Mycobacterium marinum/immunology
  • Mycobacterium marinum/pathogenicity
  • Mycobacterium tuberculosis/pathogenicity
  • Receptors, Purinergic P2X7/genetics*
  • Receptors, Purinergic P2X7/immunology
  • Signal Transduction
  • Tissue Culture Techniques
  • Tuberculosis, Pulmonary/drug therapy
  • Tuberculosis, Pulmonary/microbiology
  • Zebrafish/genetics
  • Zebrafish/immunology
  • Zebrafish/microbiology
  • Zebrafish Proteins/agonists
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/immunology
PubMed: 30693866 Full text @ Elife
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.