Reduction of host cell mitochondrial activity as <i>Mycobacterium leprae’s</i> strategy to evade host innate immunity

Oliveira, Marcus F.; Medeiros, Rychelle Clayde Affonso; Mietto, Bruno Siqueira; Leal-Calvo, Thyago; Mendonça, Ana Paula M.; Rosa, Thabatta Leal Silveira Andrezo; Silva, Débora Santos da; Vasconcelos, Karina Girardi do Carmo de; Pereira, Antônio; Macedo, Cristiana Santos de; Pereira, Geraldo M. B.; Moreira, Marcia de Berrêdo Pinho; Pessolani, Maria Cristina Vidal; Moraes, Milton Ozório; Lara, Flávio Alves

doi:10.1111/imr.12962

Cited by 18 publications

(25 citation statements)

References 156 publications

(328 reference statements)

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“…Similar to M.tb, M.leprae upregulates lipid uptake and biosynthetic pathways in infected macrophages, particularly cholesterol (88,89). Mechanistically, infection with M.leprae increases macrophage expression of scavenger receptor (SR)A-I and CD36, promoting the foamy macrophage phenotype (90,91).…”

Section: Lipid Metabolismmentioning

confidence: 99%

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Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

et al. 2021

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Mycobacterial diseases are a major public health challenge. Their causative agents include, in order of impact, members of the Mycobacterium tuberculosis complex (causing tuberculosis), Mycobacterium leprae (causing leprosy), and non-tuberculous mycobacterial pathogens including Mycobacterium ulcerans. Macrophages are mycobacterial targets and they play an essential role in the host immune response to mycobacteria. This review aims to provide a comprehensive understanding of the immune-metabolic adaptations of the macrophage to mycobacterial infections. This metabolic rewiring involves changes in glycolysis and oxidative metabolism, as well as in the use of fatty acids and that of metals such as iron, zinc and copper. The macrophage metabolic adaptations result in changes in intracellular metabolites, which can post-translationally modify proteins including histones, with potential for shaping the epigenetic landscape. This review will also cover how critical tuberculosis co-morbidities such as smoking, diabetes and HIV infection shape host metabolic responses and impact disease outcome. Finally, we will explore how the immune-metabolic knowledge gained in the last decades can be harnessed towards the design of novel diagnostic and therapeutic tools, as well as vaccines.

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Section: Lipid Metabolismmentioning

confidence: 99%

“…Notably, M.leprae infection reduces host cell mitochondrial activity in a distinctive manner (88). Oliveira et al proposed that cytosolic accumulation of lipids in M.leprae-infected macrophages may contribute to mitochondrial shutdown and suppression of their innate immune functions (88).…”

Section: Lipid Metabolismmentioning

confidence: 99%

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

et al. 2021

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“…Most individuals develop an efficient immune response to M. leprae after exposure. However, in a small number of exposed individuals, the infection may not be controlled at the mucosal sites, favoring M. leprae growth in the host cells and spreading ( Lázaro et al, 2010 ; Oliveira et al, 2021 ). Following an increase in the bacillary load, the pathogen may disseminate via bloodstream to other body parts.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the evolutionary strategy that involved the reduction in its genome to a minimal set of genes, M. leprae became dependent on the host cell metabolism, making it highly susceptible to host-target strategies such as the inhibition of cholesterol synthesis by statins, for example ( Cole et al, 2001 ; Mattos et al, 2011b ; Lobato et al, 2014 ). Medeiros et al also demonstrated that after infection, M. leprae modulates Schwann cell metabolism to a more glycolytic profile, with increased glucose uptake and consumption followed by a reduction in oxidative phosphorylation, which results in mitophagy induction ( Oliveira et al, 2021 ). All these host cell metabolic changes are crucial to the lipid accumulation and foamy aspect of infected cells, a hallmark that is crucial to M. leprae infection success.…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Response to Mycobacterium leprae and Pathogenesis of Leprosy

Cabral

Figueiredo²,

Gandini³

et al. 2022

Front. Microbiol.

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The initial infection by the obligate intracellular bacillus Mycobacterium leprae evolves to leprosy in a small subset of the infected individuals. Transmission is believed to occur mainly by exposure to bacilli present in aerosols expelled by infected individuals with high bacillary load. Mycobacterium leprae-specific DNA has been detected in the blood of asymptomatic household contacts of leprosy patients years before active disease onset, suggesting that, following infection, the bacterium reaches the lymphatic drainage and the blood of at least some individuals. The lower temperature and availability of protected microenvironments may provide the initial conditions for the survival of the bacillus in the airways and skin. A subset of skin-resident macrophages and the Schwann cells of peripheral nerves, two M. leprae permissive cells, may protect M. leprae from effector cells in the initial phase of the infection. The interaction of M. leprae with these cells induces metabolic changes, including the formation of lipid droplets, that are associated with macrophage M2 phenotype and the production of mediators that facilitate the differentiation of specific T cells for M. leprae-expressed antigens to a memory regulatory phenotype. Here, we discuss the possible initials steps of M. leprae infection that may lead to active disease onset, mainly focusing on events prior to the manifestation of the established clinical forms of leprosy. We hypothesize that the progressive differentiation of T cells to the Tregs phenotype inhibits effector function against the bacillus, allowing an increase in the bacillary load and evolution of the infection to active disease. Epigenetic and metabolic mechanisms described in other chronic inflammatory diseases are evaluated for potential application to the understanding of leprosy pathogenesis. A potential role for post-exposure prophylaxis of leprosy in reducing M. leprae-induced anti-inflammatory mediators and, in consequence, Treg/T effector ratios is proposed.

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“…Accumulating studies revealed that the antioxidant defense network alleviates oxidative stress, regulates inflammatory responses, and improves immunity by ensuring redox balance and adaptive homeostasis (21)(22)(23). The rapid development of sequencing technology offers more possibilities for identifying more valuable tumor markers (24,25).…”

Section: Introductionmentioning

confidence: 99%

Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer

Dang

Liu

et al. 2021

Front. Oncol.

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Colorectal cancer (CRC), a seriously threat that endangers public health, has a striking tendency to relapse and metastasize. Redox-related signaling pathways have recently been extensively studied in cancers. However, the study and potential role of redox in CRC remain unelucidated. We developed and validated a risk model for prognosis and recurrence prediction in CRC patients via identifying gene signatures driven by redox-related signaling pathways. The redox-driven prognostic signature (RDPS) was demonstrated to be an independent risk factor for patient survival (including OS and RFS) in four public cohorts and one clinical in-house cohort. Additionally, there was an intimate association between the risk score and tumor immune infiltration, with higher risk score accompanied with less immune cell infiltration. In this study, we used redox-related factors as an entry point, which may provide a broader perspective for prognosis prediction in CRC and have the potential to provide more promising evidence for immunotherapy.

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Reduction of host cell mitochondrial activity as Mycobacterium leprae’s strategy to evade host innate immunity

Abstract: This article is part a series of reviews covering Immunity to Mycobacteria appearing in Volume 301 of Immunological Reviews.

Cited by 18 publications

References 156 publications

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

Modulation of the Response to Mycobacterium leprae and Pathogenesis of Leprosy

Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer

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