Abstract
SummaryMycobacterium 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.
Highlights
Leprosy, like tuberculosis, presents as a granulomatous disease
M. leprae Elicits Typical Responses in Macrophages of Zebrafish Larvae To determine if zebrafish larvae might be a useful model for studying early M. leprae infection, we first examined the earliest interactions of M. leprae with phagocytes, by injecting bacteria into the caudal vein or the hindbrain ventricle (Figure 1A), where phagocytes are rarely observed in the absence of infection (Davis et al, 2002)
Aggregates of infected macrophages formed within 4 days (Figure 1B), similar to the case with M. marinum infection (Davis et al, 2002)
Summary
Like tuberculosis, presents as a granulomatous disease. These granulomas are usually cutaneous, reflecting the $30C growth optimum of M. leprae, similar to that of the human skin ($34C) (Bierman, 1936; Renault and Ernst, 2015; Truman and Krahenbuhl, 2001). M. leprae is the only mycobacterial infection that causes widespread demyelinating neuropathy, which results in the main morbidities of leprosy, including autoamputation of digits and blindness (Renault and Ernst, 2015). Understanding the pathogenesis of leprosy neuropathy has been stymied by the inability to culture M. leprae, which has undergone severe reductive evolution of its genome to become an obligate intracellular pathogen (Cole et al, 2001; Scollard et al, 2006). Our understanding of the pathogenesis of leprosy neuropathy in vivo largely comes from studies of patients; the 4- to 10-year delay in the onset of symptoms largely precludes studies of the early events that lead to neuropathy (Noordeen, 1994)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
