Phenolic glycolipid‐1 of Mycobacterium leprae is involved in human Schwann cell line ST8814 neurotoxic phenotype

Abstract

Leprosy is a chronic infectious disease caused by Mycobacterium leprae infection in Schwann cells. Axonopathy is considered a hallmark of leprosy neuropathy and is associated with the irreversible motor and sensory loss seen in infected patients.Although M. leprae is recognized to provoke Schwann cell dedifferentiation, the mechanisms involved in the contribution of this phenomenon to neural damage remain unclear. In the present work, we used live M. leprae to infect the immortalized human Schwann cell line ST8814. The neurotoxicity of infected Schwann cell-conditioned medium (SCCM) was then evaluated in a human neuroblastoma cell lineage and mouse neurons. ST8814 Schwann cells exposed to M. leprae affected neuronal viability by deviating glial 14 C-labeled lactate, important fuel of neuronal central metabolism, to de novo lipid synthesis. The phenolic glycolipid-1 (PGL-1) is a specific M. leprae cell wall antigen proposed to mediate bacterial-Schwann cell interaction. Therefore, we assessed the role of the PGL-1 on Schwann cell phenotype by using transgenic M. bovis (BCG)-expressing the M. leprae PGL-1. We observed that BCG-PGL-1 was able to induce a phenotype similar to M. leprae, unlike the wild-type BCG strain. We next demonstrated that this Schwann cell neurotoxic phenotype, induced by M. leprae PGL-1, occurs through the protein kinase B (Akt) pathway. Interestingly, the pharmacological inhibition of Akt by triciribine significantly reduced free fatty acid content in the SCCM from M. leprae-and BCG-PGL-1-infected Schwann cells and, hence, preventing neuronal death. Overall, these findings provide novel evidence that both M. leprae and PGL-1, induce a toxic Schwann cell phenotype, by modifying the host lipid metabolism, resulting in profound implications for neuronal loss. We consider this metabolic rewiring a new molecular mechanism to be the basis of leprosy neuropathy.

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

“… Medeiros et al (2016) observed that infected human ST8814 Schwann cells secrete less lactate than uninfected cells. Girardi et al (2023) confirmed this by determining the fate of lactate within the metabolism reprogramming. In this study, lactate supplementation was associated with an increase in intracellular lipid body deposition.…”

“…Activated phosphoinositide 3-kinase (PI3K), in turn, activates PKB/AKT, an enzyme that controls lipid homeostasis by activation of ATP-citrate lyase, which converts citrate to acetyl-CoA, the first step of lipid synthesis. Girardi et al (2023) , through investigation of the downstream elements of this cascade, showed higher phosphorylated AKT (p-AKT) in live M. leprae -infected human Schwann cell protein extracts in comparison to the that of the non-stimulated control group. Furthermore, the use of the AKT-phosphorylation inhibitor triciribine reverted the lactate deviation to fatty acids through PI3K/AKT signaling, corroborating the role of this pathway in metabolism remodeling.…”

“…Among the significantly modulated genes, the authors observed 11 genes involved in the oxidative phosphorylation pathway, including 7 targets related to mitochondria. More recently, another study demonstrated the relationship between the lactate carbon deviation to long chain fatty acid synthesis, and its negative impact on neurons ( Girardi et al, 2023 ).…”

“…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 ).…”

Editorial: Promoting nervous system regeneration by treatments targeting neuron-glia interactions

“…Interestingly, studies on PNS regeneration suggest that Schwann cells coordinate the healing process and adopt a cellular phenotype that favors removal of debris, neuronal survival, axon regeneration, remyelination, transfer of cargos, among many other aspects (Mietto et al, 2015 , 2021 ; Jessen and Mirsky, 2019 ; Babetto et al, 2020 ; Bombeiro et al, 2020a , b ; Sardella-Silva et al, 2021 ). Conversely, perturbed Schwann cells metabolism is linked to axonal pathology (Viader et al, 2013 ; Girardi et al, 2023 ). Therefore, regeneration of PNS has taught us many lessons, some of them reviewed in Neuron-Schwann interaction in peripheral nervous system homeostasis, disease, and preclinical treatment ( Oliveira et al ).…”