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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Matty, MA; Knudsen, DR; Walton, EM; Beerman, RW; Cronan, MR; Pyle, CJ; Hernandez, RE; Tobin, DM

Published Date

  • January 29, 2019

Published In

Volume / Issue

  • 8 /

PubMed ID

  • 30693866

Pubmed Central ID

  • 30693866

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.39123

Language

  • eng

Conference Location

  • England