03429nas a2200349   4500000000100000008004100001260001200042653001500054653001200069653002000081653001500101653001700116653001800133653000900151653000800160100001500168700001100183700001300194700001300207700001200220700001300232700001300245700001400258700001100272700001500283700001700298245016600315300001100481490000800492520256500500022001403065       2022                            d  c03/202210aArmadillos10aAxotomy10aEpidermal nerve10atratamento10aRegeneration10aSchwann Cells10aSkin10ap751 aEbenezer G1 aPena M1 aDaniel A1 aTruman R1 aAdams L1 aDuthie M1 aWagner K1 aZampino S1 aTolf E1 aTsottles D1 aPolydefkis M00aMycobacterium leprae induces Schwann cell proliferation and migration in a denervated milieu following intracutaneous excision axotomy in nine-banded armadillos.  a1140530 v3523 a<p>Nine-banded armadillos develop peripheral neuropathy after experimental Mycobacterium leprae infection that recapitulates human disease. We used an intracutaneous excision axotomy model to assess the effect of infection duration by M. leprae on axonal sprouting and Schwan cell density. 34 armadillos (17 naïve and 17&nbsp;M. leprae-infected) underwent 3&nbsp;mm skin biopsies to create an intracutaneous excision axotomy followed by a concentric 4-mm overlapping biopsy 3 and 12-months post M. leprae inoculation. A traditional distal leg biopsy was obtained at 15mo for intraepidermal nerve fiber (IENF) density. Serial skin sections were immunostained against a axons (PGP9.5, GAP43), and Schwann cells (p75, s100) to visualize regenerating nerves. Regenerative axons and proliferation of Schwann cells was measured and the rate of growth at each time point was assessed. Increasing anti-PGL antibody titers and intraneural M. leprae confirmed infection. 15mo following infection, there was evidence of axon loss with reduced distal leg IENF versus naïve armadillos, p&nbsp;&lt;&nbsp;0.05. This was associated with an increase in Schwann cell density (11,062&nbsp;±&nbsp;2905 vs. 7561&nbsp;±&nbsp;2715 cells/mm, p&nbsp;&lt;&nbsp;0.01). Following excisional biopsy epidermal reinnervation increased monotonically at 30, 60 and 90&nbsp;days; the regeneration rate was highest at 30&nbsp;days, and decreased at 60 and 90&nbsp;days. The reinnervation rate was highest among animals infected for 3mo vs those infected for 12mo or naïve animals (mean&nbsp;±&nbsp;SD, 27.8&nbsp;±&nbsp;7.2 vs.16.2&nbsp;±&nbsp;5.8vs. 15.3&nbsp;±&nbsp;6.5&nbsp;mm/mm, p&nbsp;&lt;&nbsp;0.05). The infected armadillos displayed a sustained Schwann cell proliferation across axotomy time points and duration of infection (3mo:182&nbsp;±&nbsp;26, 12mo: 256&nbsp;±&nbsp;126, naive: 139&nbsp;±&nbsp;49 cells/day, p&nbsp;&lt;&nbsp;0.05). M. leprae infection is associated with sustained Schwann cell proliferation and distal limb nerve fiber loss. Rates of epidermal reinnervation were highest 3mo after infection and normalized by 12 mo of infection. We postulate that excess Schwann cell proliferation is the main pathogenic process and is deleterious to sensory axons. There is a compensatory initial increase in regeneration rates that may be an attempt to compensate for the injury, but it is not sustained and eventually followed by axon loss. Aberrant Schwann cell proliferation may be a novel therapeutic target to interrupt the pathogenic cascade of M. leprae.</p>
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