Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection
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 mov...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/39123 |
| _version_ | 1811202952953593856 |
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| author | Molly A Matty Daphne R Knudsen Eric M Walton Rebecca W Beerman Mark R Cronan Charlie J Pyle Rafael E Hernandez David M Tobin |
| author_facet | Molly A Matty Daphne R Knudsen Eric M Walton Rebecca W Beerman Mark R Cronan Charlie J Pyle Rafael E Hernandez David M Tobin |
| author_sort | Molly A Matty |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:46:20Z |
| format | Article |
| id | doaj.art-8861276875c848aca98d4ec17b2b452f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:46:20Z |
| publishDate | 2019-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8861276875c848aca98d4ec17b2b452f2022-12-22T03:51:09ZengeLife Sciences Publications LtdeLife2050-084X2019-01-01810.7554/eLife.39123Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infectionMolly A Matty0https://orcid.org/0000-0002-4542-2800Daphne R Knudsen1Eric M Walton2Rebecca W Beerman3Mark R Cronan4Charlie J Pyle5Rafael E Hernandez6https://orcid.org/0000-0003-4408-7411David M Tobin7https://orcid.org/0000-0003-3465-5518Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States; University Program in Genetics and Genomics, Duke University, Durham, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United StatesCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United StatesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States; Department of Immunology, Duke University School of Medicine, Durham, United StatesMycobacterium 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.https://elifesciences.org/articles/39123mycobacteriumhost-directed therapiesphenotypic drug screeningzebrafishlight sheet microscopyp2rx7 |
| spellingShingle | Molly A Matty Daphne R Knudsen Eric M Walton Rebecca W Beerman Mark R Cronan Charlie J Pyle Rafael E Hernandez David M Tobin Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection eLife mycobacterium host-directed therapies phenotypic drug screening zebrafish light sheet microscopy p2rx7 |
| title | Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection |
| title_full | Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection |
| title_fullStr | Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection |
| title_full_unstemmed | Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection |
| title_short | Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection |
| title_sort | potentiation of p2rx7 as a host directed strategy for control of mycobacterial infection |
| topic | mycobacterium host-directed therapies phenotypic drug screening zebrafish light sheet microscopy p2rx7 |
| url | https://elifesciences.org/articles/39123 |
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