Effect of Mycobacterium leprae on neurotrophins expression in human Schwann cells and mouse sciatic nerves

Abstract

BACKGROUND Although Mycobacterium leprae (ML) is well characterised as the causative agent of leprosy, the pathophysiological mechanisms underlying peripheral nerve damage still need further understanding. In vitro and in vivo studies have yielded insights into molecular mechanisms of ML interaction with Schwann cells (SC), indicating the regulation of genes and proteins crucial to neural plasticity. OBJECTIVES We aimed to investigate the effect of ML on neurotrophins expression in human SC (hSC) and mice sciatic nerves to better understand their role in leprosy neuropathy, and aiming to contribute to future therapeutic approaches. METHODS We evaluated mRNA and protein expression of BDNF, NGF, NT-3, NT-4 in hSC from amputation nerve fragments, as well as in athymic nude mice, infected by ML for eight months. FINDINGS and MAIN CONCLUSIONS Our in vitro results showed a trend to decline in NGF and BDNF mRNA in ML-treated hSC, compared to controls. The immunodetection of BDNF and NT-4 was significantly downregulated in ML-treated hSC. Conversely, ML-infected mice demonstrated upregulation of NT-3, compared to non-infected animals. Our findings indicate that ML may be involved in neurotrophins regulation, suggesting that a pathogen-related imbalance of these growth factors may have a role in the neural impairment of leprosy.

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy

“…By examining the mRNA profile involved in Schwann cell dedifferentiation, we observed that cJUN, GDNF, and MAPK14 were statistically upregulated, while ERBB2, GJA1, BDNF, and MAPK3 were significantly decreased in nerves from PNL patients. Although neurotrophins, such as BDNF, are required for axon regeneration, here we found that BDNF was downregulated in PNL patients, which is in agreement with a previous report that investigated neurotrophin expression in leprosy infection (34).…”

What happens when Schwann cells are exposed to Mycobacterium leprae – A systematic review

“…In addition to that, work from Singh et al (1997a) , using primary Schwann cells from two mouse strains (SW and C57BL/6) observed that live M. leprae infection did not affect the protein levels of the neurotrophic factor, nerve growth factor (NGF), when compared to those of non-infected control cultures. Moreover, in a recent study using human primary Schwann cells, Nogueira et al (2020) observed that exposure to sonicated M. leprae significantly reduced neurotrophin (NT)-4 and brain-derived neurotrophic factor protein levels at 48 h, when compared to the levels of non-infected cells, while not affecting the expression profile of NGF and NT-3.…”

“…M. leprae has a unique predilection to infect non-myelinating and myelinating Schwann cells, the enwrapping glia of the peripheral nervous system ( Hagge et al, 2002 , Hess and Rambukkana, 2019 , Mietto et al, 2020 ). Once intracellular, this pathogen provokes multiple alterations in Schwann cells, affecting both early and late cellular events, including modifications in the glucose and lipid metabolism and trafficking ( Medeiros et al, 2016 , Rosa et al, 2021 , Girardi et al, 2023 ), myelin dismantling and lipid droplet accumulation ( Tapinos et al, 2006 , Mattos et al, 2011a , Elamin et al, 2012 , Jin et al, 2017 , Mietto et al, 2020 ), neurotrophin secretion ( Nogueira et al, 2020 ), and changes in gene expression ( Casalenovo et al, 2019 , de Souza et al, 2022 ), leading to Schwann cell reprogramming to an immature, highly proliferative phenotype ( Hess and Rambukkana, 2019 ). Interestingly, the progression of leprosy neuropathy occurs even after the end of the treatment and achievement of clinical cure ( Penna et al, 2023 ).…”