Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection

• Published in: eLife Vol. 8
• Main Authors: Matty, Molly A, Knudsen, Daphne R, Walton, Eric M, Beerman, Rebecca W, Cronan, Mark R, Pyle, Charlie J, Hernandez, Rafael E, Tobin, David M
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 29.01.2019; eLife Sciences Publications, Ltd
• Subjects: Animals; Anti-Allergic Agents - pharmacology; Antibiotics; Antitubercular Agents - pharmacology; Calcium; Calcium - immunology; Calcium - metabolism; Cell culture; Clemastine - pharmacology; Clinical trials; Danio rerio; Disease Models, Animal; Drug Repositioning; Drug resistance; Experiments; Gene Expression Regulation; Genomics; Granuloma - drug therapy; Granuloma - genetics; Granuloma - immunology; Granuloma - microbiology; host-directed therapies; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate - drug effects; Immunology and Inflammation; Infections; Inflammasomes; Larva - drug effects; Larva - genetics; Larva - immunology; Larva - microbiology; Larvae; light sheet microscopy; Light therapy; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - microbiology; Medical research; Microbiology and Infectious Disease; Mutation; mycobacterium; 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; p2rx7; phenotypic drug screening; Public health; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - immunology; Signal Transduction; Tissue Culture Techniques; Tuberculosis; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - microbiology; zebrafish; Zebrafish - genetics; Zebrafish - immunology; Zebrafish - microbiology; Zebrafish Proteins - agonists; Zebrafish Proteins - genetics; Zebrafish Proteins - immunology; United States > US; mycobacterium; infectious disease; inflammation; host-directed therapies; microbiology; zebrafish; phenotypic drug screening; immunology; light sheet microscopy; p2rx7
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.39123

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- 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.