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

Autor:	Rosa TLSA; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Marques MAM; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., DeBoard Z; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Hutchins K; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Silva CAA; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Montague CR; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, United States., Yuan T; Department of Chemistry, Stony Brook University, Stony Brook, NY, United States., Amaral JJ; Laboratório de Química Biológica, Diretoria de Metrologia Aplicada às Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia, Rio de Janeiro, Brazil., Atella GC; Laboratório de Bioquímica de Lipídeos e Lipoproteínas, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Rosa PS; Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, Bauru, Brazil., Mattos KA; Departmento de Controle de Qualidade, Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., VanderVen BC; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, United States., Lahiri R; Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Programs, Baton Rouge, LA, United States., Sampson NS; Department of Chemistry, Stony Brook University, Stony Brook, NY, United States., Brennan PJ; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Belisle JT; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Pessolani MCV; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Berrêdo-Pinho M; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular and infection microbiology [Front Cell Infect Microbiol] 2021 Jul 28; Vol. 11, pp. 709972. Date of Electronic Publication: 2021 Jul 28 (Print Publication: 2021).
DOI:	10.3389/fcimb.2021.709972
Abstrakt:	Upon infection, Mycobacterium leprae , an obligate intracellular bacillus, induces accumulation of cholesterol-enriched lipid droplets (LDs) in Schwann cells (SCs). LDs are promptly recruited to M. leprae -containing phagosomes, and inhibition of this process decreases bacterial survival, suggesting that LD recruitment constitutes a mechanism by which host-derived lipids are delivered to intracellular M. leprae . We previously demonstrated that M. leprae has preserved only the capacity to oxidize cholesterol to cholestenone, the first step of the normal cholesterol catabolic pathway. In this study we investigated the biochemical relevance of cholesterol oxidation on bacterial pathogenesis in SCs. Firstly, we showed that M. leprae increases the uptake of LDL-cholesterol by infected SCs. Moreover, fluorescence microscopy analysis revealed a close association between M. leprae and the internalized LDL-cholesterol within the host cell. By using Mycobacterium smegmatis mutant strains complemented with M. leprae genes, we demonstrated that ml1942 coding for 3β-hydroxysteroid dehydrogenase (3β-HSD), but not ml0389 originally annotated as cholesterol oxidase (ChoD), was responsible for the cholesterol oxidation activity detected in M. leprae . The 3β-HSD activity generates the electron donors NADH and NADPH that, respectively, fuel the M. leprae respiratory chain and provide reductive power for the biosynthesis of the dominant bacterial cell wall lipids phthiocerol dimycocerosate (PDIM) and phenolic glycolipid (PGL)-I. Inhibition of M. leprae 3β-HSD activity with the 17β-[N-(2,5-di-t-butylphenyl)carbamoyl]-6-azaandrost-4-en-3one (compound 1), decreased bacterial intracellular survival in SCs. In conclusion, our findings confirm the accumulation of cholesterol in infected SCs and its potential delivery to the intracellular bacterium. Furthermore, we provide strong evidence that cholesterol oxidation is an essential catabolic pathway for M. leprae pathogenicity and point to 3β-HSD as a prime drug target that may be used in combination with current multidrug regimens to shorten leprosy treatment and ameliorate nerve damage. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Rosa, Marques, DeBoard, Hutchins, Silva, Montague, Yuan, Amaral, Atella, Rosa, Mattos, VanderVen, Lahiri, Sampson, Brennan, Belisle, Pessolani and Berrêdo-Pinho.)
Databáze:	MEDLINE
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