Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis

Rosa, Thabatta Leal Silveira Andrezo; Marques, Maria Angela M.; DeBoard, Zachary; Hutchins, Kelly; Silva, Carlos Adriano A.; Montague, Christine R; Yuan, Tianao; Amaral, Julio Jablonski; Atella, Geórgia C.; Rosa, Patrícia Sammarco; Mattos, Katherine Antunes de; VanderVen, Brian C.; Lahiri, Ramanuj; Sampson, Nicole S.; Brennan, Patrick J.; Belisle, John T.; Pessolani, Maria Cristina Vidal; Berrêdo-Pinho, Márcia

doi:10.3389/fcimb.2021.709972

Cited by 14 publications

(16 citation statements)

References 57 publications

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“…Of importance, this immunomodulation profile seen in infected Schwann cells was reported to occur before the reprogramming of the Schwann cells to the immature phenotype, highlighting the crucial role of the immune signaling network in the context of the early stages of M. leprae infection (16,17). Additionally, M. leprae infection of Schwann cells has been associated with alterations in the glucose/lactate metabolic pathway (18,19), lipid/cholesterol accumulation (20,21), mitochondrial dysfunction (11), and myelin dismantling (22)(23)(24). Some of these changes were also confirmed in leprosy patients, and are suggested to cause the ongoing neuropathy and the observed tissue fibrosis and loss of nerve function experienced by leprosy individuals (14,25).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Peripheral neuropathy is the main cause of physical disability in leprosy patients. Importantly, the extension and pattern of peripheral damage has been linked to how the host cell will respond against Mycobacterium leprae (M. leprae) infection, in particular, how the pathogen will establish infection in Schwann cells. Interestingly, viable and dead M. leprae have been linked to neuropathology of leprosy by distinct mechanisms. While viable M. leprae promotes transcriptional modifications that allow the bacteria to survive through the use of the host cell's internal machinery and the subvert of host metabolites, components of the dead bacteria are associated with the generation of a harmful nerve microenvironment. Therefore, understanding the pathognomonic characteristics mediated by viable and dead M. leprae are essential for elucidating leprosy disease and its associated reactional episodes. Moreover, the impact of the viable and dead bacteria in Schwann cells is largely unknown and their gene signature profiling has, as yet, been poorly explored. In this study, we analyzed the early differences in the expression profile of genes involved in peripheral neuropathy, dedifferentiation and plasticity, neural regeneration, and inflammation in human Schwann cells challenged with viable and dead M. leprae. We substantiated our findings by analyzing this genetic profiling in human nerve biopsies of leprosy and non-leprosy patients, with accompanied histopathological analysis. We observed that viable and dead bacteria distinctly modulate Schwann cell genes, with emphasis to viable bacilli upregulating transcripts related to glial cell plasticity, dedifferentiation and anti-inflammatory profile, while dead bacteria affected genes involved in neuropathy and pro-inflammatory response. In addition, dead bacteria also upregulated genes associated with nerve support, which expression profile was similar to those obtained from leprosy nerve biopsies. These findings suggest that early exposure to viable and dead bacteria may provoke Schwann cells to behave differentially, with far-reaching implications for the ongoing neuropathy seen in leprosy patients, where a mixture of active and non-active bacteria are found in the nerve microenvironment.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Considering these observations, 6-azasteroids were screened for potentiation activity with isoniazid and BDQ against Mtb 3β-Hsd knockout mutants, and potentiation activity was found to be maintained, indicating that 3β-Hsd is not a key target of 6-azasteroids . More recently, 6-azasteroids have been shown to inhibit Mycobacterium leprae, which has no cholesterol catabolism genes other than a gene for a 3β-Hsd homologue that shares greater than 75% amino acid identity with Mtb 3β-Hsd.…”

Section: Resultsmentioning

confidence: 99%

A Chemoproteomic Approach to Elucidate the Mechanism of Action of 6-Azasteroids with Unique Activity in Mycobacteria

Werman,

Chen,

Yuan

et al. 2023

ACS Infect. Dis.

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By illuminating key 6-azasteroid−protein interactions in both Mycobacterium tuberculosis (Mtb) and the closely related model organism Mycobacterium marinum (Mm), we sought to improve the antimycobacterial potency of 6-azasteroids and further our understanding of the mechanisms responsible for their potentiation of the antituberculosis drug bedaquiline. We selected a newly developed 6-azasteroid analog and an analog reported previously (ACS Infect. Dis. 2019, 5 (7), 1239−1251) to study their phenotypic effects on Mtb and Mm, both alone and in combination with bedaquiline. The 6-azasteroid analog, 17β-[N-(4trifluoromethoxy-diphenylmethyl)carbamoyl]-6-propyl-azaandrostan-3-one, robustly potentiated bedaquiline-mediated antimycobacterial activity, with a nearly 8-fold reduction in Mm bedaquiline minimal inhibitory concentration (85 nM alone versus 11 nM with 20 μM 6-azasteroid). This analog displayed minimal inhibitory activity against recombinant mycobacterial 3β-hydroxysteroid dehydrogenase, a previously identified target of several 6-azasteroids. Dose-dependent potentiation of bedaquiline by this analog reduced mycobacterial intracellular ATP levels and impeded the ability of Mtb to neutralize exogenous oxidative stress in culture. We developed two 6-azasteroid photoaffinity probes to investigate azasteroid−protein interactions in Mm whole cells. Using bottom-up mass spectrometric profiling of the cross-linked proteins, we identified eight potential Mm/Mtb protein targets for 6-azasteroids. The nature of these potential targets indicates that proteins related to oxidative stress resistance play a key role in the BDQ-potentiating activity of azasteroids and highlights the potential impact of inhibition of these targets on the generation of drug sensitivity.

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“…Since 3β-Hsd can also oxidize oxysterols, such as pregnenolone ( 29 ), M. tuberculosis might also modify steroid hormones. Interestingly, Mycobacterium leprae has lost the genes for cholesterol catabolism, but retains hsd and the ability to make cholestenone ( 50 , 51 ). In addition, in M. tuberculosis Rv1106c/ hsd is not transcriptionally regulated with other genes required for cholesterol metabolism ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Macrophage global metabolomics identifies cholestenone as host/pathogen cometabolite present in human Mycobacterium tuberculosis infection

Chandra¹,

Coullon²,

Agarwal³

et al. 2022

Journal of Clinical Investigation

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Mycobacterium tuberculosis ( M. tuberculosis ) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other’s metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis –infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3 β -hydroxysteroid dehydrogenase (3 β -Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis –infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis , we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.

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Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis

Cited by 14 publications

References 57 publications

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

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

A Chemoproteomic Approach to Elucidate the Mechanism of Action of 6-Azasteroids with Unique Activity in Mycobacteria

Macrophage global metabolomics identifies cholestenone as host/pathogen cometabolite present in human Mycobacterium tuberculosis infection

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