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dc.contributor.authorRamakrishnan, Lalitaen
dc.contributor.authorMadigan, CAen
dc.contributor.authorCambier, CJen
dc.contributor.authorKelly-Scumpia, KMen
dc.contributor.authorScumpia, POen
dc.contributor.authorCheng, T-Yen
dc.contributor.authorZailaa, Jen
dc.contributor.authorBloom, BRen
dc.contributor.authorMoody, DBen
dc.contributor.authorSmale, STen
dc.contributor.authorSagasti, Aen
dc.contributor.authorModlin, RLen
dc.date.accessioned2017-08-15T13:20:25Z
dc.date.available2017-08-15T13:20:25Z
dc.date.issued2017-08-24en
dc.identifier.issn0092-8674
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266416
dc.description.abstract$\textit{Mycobacterium leprae}$ 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 $\textit{M. leprae}$-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 $\textit{M. leprae}$-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by $\textit{M. leprae}$ 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 $\textit{M. marinum}$-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 $\textit{M. leprae}$ PGL-1 in initiating nerve damage in leprosy.
dc.description.sponsorshipThis work was supported by an A.P. Giannini Foundation Postdoctoral Fellowship, an NIH training grant (T32 AI1007411), and an NIH NRSA Postdoctoral Fellowship (AI104240) to C.A.M.; an NSF Predoctoral Fellowship and NIH training grant T32 AI55396 to C.J.C.; a UCLA Clinical Translational Science Institute grant (UL1TR001881 to K.K.S.); K08AR066545 to P.O.S.; U19AI111224 and R01AI049313 to D.B.M.; an NIH grant (R01AR064582) to A.S.; the NIH Director’s Pioneer Award, an NIH MERIT award (R37AI054503), and a Wellcome Trust Principal Research Fellowship to L.R.
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleA Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosyen
dc.typeArticle
prism.endingPage985.e10
prism.issueIdentifier5en
prism.publicationDate2017en
prism.publicationNameCellen
prism.startingPage973
prism.volume170en
dc.identifier.doi10.17863/CAM.12101
dcterms.dateAccepted2017-07-22en
rioxxterms.versionofrecord10.1016/j.cell.2017.07.030en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-08-24en
dc.contributor.orcidRamakrishnan, Lalita [0000-0003-0692-5533]
dc.identifier.eissn1097-4172
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (103950/Z/14/Z)
cam.issuedOnline2017-08-25en
cam.orpheus.successThu Jan 30 12:59:18 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International