TY - JOUR T1 - A macrophage response to <em>Mycobacterium leprae</em> phenolic glycolipid initiates nerve damage in leprosy JF - bioRxiv DO - 10.1101/127944 SP - 127944 AU - Cressida A. Madigan AU - C.J. Cambier AU - Kindra M. Kelly-Scumpia AU - Philip O. Scumpia AU - Tan-Yun Cheng AU - Joseph Zailaa AU - Barry R. Bloom AU - D. Branch Moody AU - Steven T. Smale AU - Alvaro Sagasti AU - Robert L. Modlin AU - Lalita Ramakrishnan Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/17/127944.abstract N2 - 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 interactions 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. ER -