The Immunoregulatory Actions of DHEA in Tuberculosis, A Tool for Therapeutic Intervention?

Bongiovanni, Bettina; Díaz, Ariana; Santucci, Natalia; D’Attilio, Luciano; Hernández-Pando, Rogelio; Bay, María Luisa

doi:10.3389/fendo.2022.892270

Cited by 7 publications

(6 citation statements)

References 78 publications

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“…These results provide molecular support to our previous reports in the BALB/C mouse TB model. In this previous report, a new water-miscible formulation of Br-DHEA resulted in lowered pneumonia and, greater and, fast bacterial clearance, along with a reduction of 11β-HSD1 activity and corticosterone production that effectively reactivates the protective anti-TB immunity ( 59 , 79 ).…”

Section: Discussionmentioning

confidence: 93%

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

Hernández-Bustamante

Santander-Plantamura²,

Mata-Espinosa³

et al. 2023

Front. Endocrinol.

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Metabolic syndrome is considered the precursor of type 2 diabetes mellitus. Tuberculosis is a leading infection that constitutes a global threat remaining a major cause of morbi-mortality in developing countries. People with type 2 diabetes mellitus are more likely to suffer from infection with Mycobacterium tuberculosis. For both type 2 diabetes mellitus and tuberculosis, there is pulmonary production of anti-inflammatory glucocorticoids mediated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal hormone dehydroepiandrosterone (DHEA) counteracts the glucocorticoid effects of cytokine production due to the inhibition of 11β-HSD1. Late advanced tuberculosis has been associated with the suppression of the Th1 response, evidenced by a high ratio of cortisol/DHEA. In a murine model of metabolic syndrome, we determined whether DHEA treatment modifies the pro-inflammatory cytokines due to the inhibition of the 11β-HSD1 expression. Since macrophages express 11β-HSD1, our second goal was incubating them with DHEA and Mycobacterium tuberculosis to show that the microbicide effect was increased by DHEA. Enoyl-acyl carrier protein reductase (InhA) is an essential enzyme of Mycobacterium tuberculosis involved in the mycolic acid synthesis. Because 11β-HSD1 and InhA are members of a short-chain dehydrogenase/reductase family of enzymes, we hypothesize that DHEA could be an antagonist of InhA. Our results demonstrate that DHEA has a direct microbicide effect against Mycobacterium tuberculosis; this effect was supported by in silico docking analysis and the molecular dynamic simulation studies between DHEA and InhA. Thus, DHEA increases the production of pro-inflammatory cytokines in the lung, inactivates GC by 11β-HSD1, and inhibits mycobacterial InhA. The multiple functions of DHEA suggest that this hormone or its synthetic analogs could be an efficient co-adjuvant for tuberculosis treatment.

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Section: Discussionmentioning

confidence: 93%

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

Hernández-Bustamante

Santander-Plantamura²,

Mata-Espinosa³

et al. 2023

Front. Endocrinol.

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show abstract

“…It is a non-androgenic, non-anabolic steroid also known as BEA (16-bromoepiandrosterone). By acting to restore homeostasis to dysregulated metabolic/immune signaling networks BEA may provide a more youthful metabolome and immune phenotype [203] as demonstrated with an improved response to tuberculosis infection [204][205][206][207].…”

Section: Treating Map/hervmentioning

confidence: 99%

<em>Mycobacterium paratuberculosis</em>: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

Dow,

Pierce,

Sechi

2024

Preprint

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Human endogenous retroviruses (HERV) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV promoting pathological conditions including the development of autoimmunity, neurodegenerative disease and cancer. What infections then trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases Crohn’s, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis and autoimmune thyroiditis. MAP is also associated with Parkinson’s disease. Autoimmune diabetes, multiple sclerosis and rheumatoid arthritis are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via unsilencing of HERV. We examine the link between the ever-increasing number of MAP- associated diseases, the MAP/HERV intersection with these diverse medical conditions and propose treatment opportunities based upon this association.

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“…Cortisol may trigger HERV-associated diseases [208,209]; thus, efforts to develop a DHEA analog to increase the DHEA/cortisol ratio reminiscent of youth may alleviate many of the diseases presented in this article by restoring immune and metabolic homeostasis.…”

Section: Treating Map/hervmentioning

confidence: 99%

<em>Mycobacterium paratuberculosis</em>: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

Dow,

Pierce,

Sechi

2024

Preprint

View full text Add to dashboard Cite

Human endogenous retroviruses (HERV) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV promoting pathological conditions including the devel-opment of autoimmunity, neurodegenerative disease and cancer. What infections then trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granu-lomatous diseases Crohn’s, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis and autoimmune thyroiditis. MAP is also associated with Parkinson’s disease. Autoimmune diabetes, multiple sclerosis and rheumatoid arthritis are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via unsilencing of HERV. We examine the link between the ever-increasing number of MAP- associated diseases, the MAP/HERV intersection with these diverse medical conditions and propose treatment opportunities based upon this association.

show abstract

The Immunoregulatory Actions of DHEA in Tuberculosis, A Tool for Therapeutic Intervention?

Cited by 7 publications

References 78 publications

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

<em>Mycobacterium paratuberculosis</em>: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

<em>Mycobacterium paratuberculosis</em>: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

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