例如:"lncRNA", "apoptosis", "WRKY"

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

Elife. 2019 Jan 29;8
Molly A Matty 1 , Daphne R Knudsen 2 , Eric M Walton 2 , Rebecca W Beerman 2 , Mark R Cronan 2 , Charlie J Pyle 2 , Rafael E Hernandez 3 , David M Tobin 4
Molly A Matty 1 , Daphne R Knudsen 2 , Eric M Walton 2 , Rebecca W Beerman 2 , Mark R Cronan 2 , Charlie J Pyle 2 , Rafael E Hernandez 3 , David M Tobin 4
+ et al

[No authors listed]

Author information
  • 1 University Program in Genetics and Genomics, Duke University, Durham, United States.
  • 2 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States.
  • 3 Department of Pediatrics, University of Washington, Seattle, United States.
  • 4 Department of Immunology, Duke University School of Medicine, Durham, United States.

摘要


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.

KEYWORDS: host-directed therapies, immunology, infectious disease, inflammation, light sheet microscopy, microbiology, mycobacterium, p2rx7, phenotypic drug screening, zebrafish