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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.
PMID
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Authors

Mayor MeshTerms
Keywords

leprosy

macrophage

mycobacteria

myelin

nerve damage

phenolic glycolipid

zebrafish

Journal Title cell
Publication Year Start




PMID- 28841420
OWN - NLM
STAT- In-Process
DA  - 20170825
LR  - 20170825
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 170
IP  - 5
DP  - 2017 Aug 24
TI  - A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve
      Damage in Leprosy.
PG  - 973-985.e10
LID - S0092-8674(17)30866-8 [pii]
LID - 10.1016/j.cell.2017.07.030 [doi]
AB  - 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.
CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Madigan, Cressida A
AU  - Madigan CA
AD  - Division of Dermatology, Department of Medicine, David Geffen School of Medicine,
      University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of 
      Microbiology, Immunology, and Molecular Genetics, David Geffen School of
      Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA;
      Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
      Electronic address: [email protected]
FAU - Cambier, C J
AU  - Cambier CJ
AD  - Department of Immunology, University of Washington, Seattle, WA 98195, USA.
FAU - Kelly-Scumpia, Kindra M
AU  - Kelly-Scumpia KM
AD  - Division of Dermatology, Department of Medicine, David Geffen School of Medicine,
      University of California, Los Angeles, Los Angeles, CA 90095, USA.
FAU - Scumpia, Philip O
AU  - Scumpia PO
AD  - Division of Dermatology, Department of Medicine, David Geffen School of Medicine,
      University of California, Los Angeles, Los Angeles, CA 90095, USA.
FAU - Cheng, Tan-Yun
AU  - Cheng TY
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Zailaa, Joseph
AU  - Zailaa J
AD  - Department of Microbiology, Immunology, and Molecular Genetics, David Geffen
      School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095,
      USA.
FAU - Bloom, Barry R
AU  - Bloom BR
AD  - Harvard School of Public Health, Boston, MA 02115, USA.
FAU - Moody, D Branch
AU  - Moody DB
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Smale, Stephen T
AU  - Smale ST
AD  - Department of Microbiology, Immunology, and Molecular Genetics, David Geffen
      School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095,
      USA; Molecular Biology Institute, University of California, Los Angeles, Los
      Angeles, CA 90095, USA.
FAU - Sagasti, Alvaro
AU  - Sagasti A
AD  - Department of Molecular, Cell, and Developmental Biology, University of
      California, Los Angeles, Los Angeles, CA 90095, USA.
FAU - Modlin, Robert L
AU  - Modlin RL
AD  - Division of Dermatology, Department of Medicine, David Geffen School of Medicine,
      University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of 
      Microbiology, Immunology, and Molecular Genetics, David Geffen School of
      Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
FAU - Ramakrishnan, Lalita
AU  - Ramakrishnan L
AD  - Department of Microbiology, University of Washington, Seattle, WA 98195, USA;
      Department of Immunology, University of Washington, Seattle, WA 98195, USA;
      Department of Medicine, University of Washington, Seattle, WA 98195, USA; MRC
      Laboratory of Molecular Biology, Molecular Immunity Unit, Department of Medicine,
      University of Cambridge, Cambridge CB2 OQH, UK. Electronic address:
      [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
OTO - NOTNLM
OT  - leprosy
OT  - macrophage
OT  - mycobacteria
OT  - myelin
OT  - nerve damage
OT  - phenolic glycolipid
OT  - zebrafish
EDAT- 2017/08/26 06:00
MHDA- 2017/08/26 06:00
CRDT- 2017/08/26 06:00
PHST- 2017/03/26 [received]
PHST- 2017/05/13 [revised]
PHST- 2017/07/19 [accepted]
AID - S0092-8674(17)30866-8 [pii]
AID - 10.1016/j.cell.2017.07.030 [doi]
PST - ppublish
SO  - Cell. 2017 Aug 24;170(5):973-985.e10. doi: 10.1016/j.cell.2017.07.030.