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

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.

journal_name

Cell

journal_title

Cell

authors

Madigan CA,Cambier CJ,Kelly-Scumpia KM,Scumpia PO,Cheng TY,Zailaa J,Bloom BR,Moody DB,Smale ST,Sagasti A,Modlin RL,Ramakrishnan L

doi

10.1016/j.cell.2017.07.030

subject

Has Abstract

pub_date

2017-08-24 00:00:00

pages

973-985.e10

issue

5

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(17)30866-8

journal_volume

170

pub_type

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