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

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. He...

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Published ineLife 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
LanguageEnglish
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
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Abstract 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.
AbstractList 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.
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.
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.
Author Walton, Eric M
Hernandez, Rafael E
Knudsen, Daphne R
Cronan, Mark R
Matty, Molly A
Tobin, David M
Beerman, Rebecca W
Pyle, Charlie J
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  orcidid: 0000-0002-4542-2800
  surname: Matty
  fullname: Matty, Molly A
  organization: University Program in Genetics and Genomics, Duke University, Durham, United States
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  givenname: Daphne R
  surname: Knudsen
  fullname: Knudsen, Daphne R
  organization: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
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  givenname: Eric M
  surname: Walton
  fullname: Walton, Eric M
  organization: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
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  givenname: Rebecca W
  surname: Beerman
  fullname: Beerman, Rebecca W
  organization: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
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  givenname: Mark R
  surname: Cronan
  fullname: Cronan, Mark R
  organization: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
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  organization: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
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  givenname: Rafael E
  orcidid: 0000-0003-4408-7411
  surname: Hernandez
  fullname: Hernandez, Rafael E
  organization: Department of Pediatrics, University of Washington, Seattle, United States
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  givenname: David M
  orcidid: 0000-0003-3465-5518
  surname: Tobin
  fullname: Tobin, David M
  organization: Department of Immunology, Duke University School of Medicine, Durham, United States
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30693866$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright 2019, Matty et al.
2019, Matty et al. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Keywords mycobacterium
infectious disease
inflammation
host-directed therapies
microbiology
zebrafish
phenotypic drug screening
immunology
light sheet microscopy
p2rx7
Language English
License 2019, Matty et al.
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Snippet is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by...
Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long...
Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long...
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SubjectTerms 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
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Title Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection
URI https://www.ncbi.nlm.nih.gov/pubmed/30693866
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