PUBLICATION

A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy

Authors
Madigan, C.A., Cambier, C.J., Kelly-Scumpia, K.M., Scumpia, P.O., Cheng, T.Y., Zailaa, J., Bloom, B.R., Moody, D.B., Smale, S.T., Sagasti, A., Modlin, R.L., Ramakrishnan, L.
ID
ZDB-PUB-170827-7
Date
2017
Source
Cell   170: 973-985.e10 (Journal)
Registered Authors
Cambier, CJ, Madigan, Cressida, Ramakrishnan, Lalita, Sagasti, Alvaro
Keywords
leprosy, macrophage, mycobacteria, myelin, nerve damage, phenolic glycolipid, zebrafish
MeSH Terms
  • Axons/metabolism
  • Axons/pathology
  • Macrophages/immunology*
  • Nitric Oxide/metabolism
  • Glycolipids/metabolism*
  • Demyelinating Diseases
  • Animals
  • Mycobacterium leprae/physiology*
  • Larva/growth & development
  • Leprosy/immunology
  • Leprosy/microbiology*
  • Leprosy/pathology*
  • Neuroglia/metabolism
  • Neuroglia/pathology
  • Disease Models, Animal*
  • Myelin Sheath/chemistry
  • Myelin Sheath/metabolism
  • Myelin Sheath/ultrastructure
  • Antigens, Bacterial/metabolism*
  • Zebrafish
  • Mycobacterium marinum/metabolism
(all 21)
PubMed
28841420 Full text @ Cell
Abstract
Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABbacterial treatment by injection: Mycobacterium lepraeDay 5
ABbacterial treatment by injection: Mycobacterium lepraeDay 5
ABbacterial treatment by injection: Mycobacterium lepraeDay 5
ABbacterial treatment by injection: Mycobacterium marinum, chemical treatment by environment: nitric oxide donorDay 5
ABbacterial treatment by injection: Mycobacterium marinum, chemical treatment by environment: nitric oxide donorDay 5
ABbacterial treatment by injection: Mycobacterium marinum, chemical treatment by environment: S-nitroso-N-acetyl-D-penicillamineDay 5
ABbacterial treatment by injection: Mycobacterium marinum, chemical treatment by environment: S-nitroso-N-acetyl-D-penicillamineDay 5
ue2Tg (AB)bacterial treatment by injection: Mycobacterium leprae, chemical treatment by environment: potassium 2-(4-carboxylatophenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxideDay 5
ue2Tg (AB)bacterial treatment by injection: Mycobacterium leprae, chemical treatment by environment: potassium 2-(4-carboxylatophenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxideDay 5
ue2Tg (AB)bacterial treatment by injection: Mycobacterium leprae, chemical treatment by environment: N(gamma)-nitro-L-arginine methyl esterDay 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nz117TgTransgenic Insertion
    s843TgTransgenic Insertion
      ue2TgTransgenic Insertion
        w200TgTransgenic Insertion
          w201TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            1 - 1 of 1
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            Sequence Targeting Reagents
            Target Reagent Reagent Type
            ccr2MO1-ccr2MRPHLNO
            irf8MO1-irf8MRPHLNO
            myd88MO2-myd88MRPHLNO
            spi1bMO2-spi1bMRPHLNO
            spi1bMO3-spi1bMRPHLNO
            1 - 5 of 5
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            Fish
            Antibodies
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            CeruleanEFGCerulean
            EGFPEFGEGFP
            EYFPEFGEYFP
            TomatoEFGTomato
            YFPEFGYFP
            1 - 5 of 5
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            Mapping
            No data available