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ZFIN ID: ZDB-PUB-170827-7
A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy
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.
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:
  • Animals
  • Antigens, Bacterial/metabolism*
  • Axons/metabolism
  • Axons/pathology
  • Demyelinating Diseases
  • Disease Models, Animal*
  • Glycolipids/metabolism*
  • Larva/growth & development
  • Leprosy/immunology
  • Leprosy/microbiology*
  • Leprosy/pathology*
  • Macrophages/immunology*
  • Mycobacterium leprae/physiology*
  • Mycobacterium marinum/metabolism
  • Myelin Sheath/chemistry
  • Myelin Sheath/metabolism
  • Myelin Sheath/ultrastructure
  • Neuroglia/metabolism
  • Neuroglia/pathology
  • Nitric Oxide/metabolism
  • Zebrafish
PubMed: 28841420 Full text @ Cell
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.