PUBLICATION

Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism

Authors
Elks, P.M., Brizee, S., van der Vaart, M., Walmsley, S.R., van Eeden, F.J., Renshaw, S.A., and Meijer, A.H.
ID
ZDB-PUB-140224-5
Date
2013
Source
PLoS pathogens   9(12): e1003789 (Journal)
Registered Authors
Elks, Philip, Meijer, Annemarie H., Renshaw, Steve A., van der Vaart, Michiel, van Eeden, Freek
Keywords
Embryos, Neutrophils, White blood cells, Mycobacterium tuberculosis, Macrophages, Granulomas, Zebrafish, Antibodies
MeSH Terms
  • Mycobacterium Infections, Nontuberculous/genetics
  • Mycobacterium Infections, Nontuberculous/immunology*
  • Mycobacterium Infections, Nontuberculous/microbiology
  • Nitric Oxide/metabolism*
  • Mycobacterium marinum*
  • Cells, Cultured
  • Neutrophils/metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit/physiology*
  • Signal Transduction/genetics
  • Disease Models, Animal
  • Basic Helix-Loop-Helix Transcription Factors/physiology
  • Animals
  • Animals, Genetically Modified
  • Zebrafish
  • Nitrosation
  • Nitric Oxide Synthase Type II/physiology
  • Genetic Predisposition to Disease
(all 17)
PubMed
24367256 Full text @ PLoS Pathog.
Abstract

Tuberculosis is a current major world-health problem, exacerbated by the causative pathogen, Mycobacterium tuberculosis (Mtb), becoming increasingly resistant to conventional antibiotic treatment. Mtb is able to counteract the bactericidal mechanisms of leukocytes to survive intracellularly and develop a niche permissive for proliferation and dissemination. Understanding of the pathogenesis of mycobacterial infections such as tuberculosis (TB) remains limited, especially for early infection and for reactivation of latent infection. Signaling via hypoxia inducible factor α (HIF-α) transcription factors has previously been implicated in leukocyte activation and host defence. We have previously shown that hypoxic signaling via stabilization of Hif-1α prolongs the functionality of leukocytes in the innate immune response to injury. We sought to manipulate Hif-α signaling in a well-established Mycobacterium marinum (Mm) zebrafish model of TB to investigate effects on the host's ability to combat mycobacterial infection. Stabilization of host Hif-1α, both pharmacologically and genetically, at early stages of Mm infection was able to reduce the bacterial burden of infected larvae. Increasing Hif-1α signaling enhanced levels of reactive nitrogen species (RNS) in neutrophils prior to infection and was able to reduce larval mycobacterial burden. Conversely, decreasing Hif-2α signaling enhanced RNS levels and reduced bacterial burden, demonstrating that Hif-1α and Hif-2α have opposing effects on host susceptibility to mycobacterial infection. The antimicrobial effect of Hif-1α stabilization, and Hif-2α reduction, were demonstrated to be dependent on inducible nitric oxide synthase (iNOS) signaling at early stages of infection. Our findings indicate that induction of leukocyte iNOS by stabilizing Hif-1α, or reducing Hif-2α, aids the host during early stages of Mm infection. Stabilization of Hif-1α therefore represents a potential target for therapeutic intervention against tuberculosis.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
i114TgTransgenic Insertion
    nz50TgTransgenic Insertion
      sh144TgTransgenic Insertion
        ump2TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          nos2aMO3-nos2aMRPHLNO
          1 - 1 of 1
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          Fish
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab1-lcp1polyclonalRabbit
          Ab1-nitrotyrosinepolyclonal
            IgGRabbit
            Ab2-nospolyclonal
              Rabbit
              1 - 3 of 3
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              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              DsRed2EFGDsRed2
              EGFPEFGEGFP
              GFPEFGGFP
              mCherryEFGmCherry
              1 - 4 of 4
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              Mapping
              No data available