<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

ABSTRACT The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes...

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Autores principales:	Priyanka Tyagi, Virender Kumar Pal, Ragini Agrawal, Shalini Singh, Sandhya Srinivasan, Amit Singh
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	glutathione redox potential extracellular acidification rate oxidative phosphorylation roGFP Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bb6c30229a30454a9ed868b2b816b07d
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spelling	oai:doaj.org-article:bb6c30229a30454a9ed868b2b816b07d2021-11-15T15:57:02Z<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics10.1128/mBio.03293-192150-7511https://doaj.org/article/bb6c30229a30454a9ed868b2b816b07d2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03293-19https://doaj.org/toc/2150-7511ABSTRACT The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant—N-acetyl cysteine (NAC)—or with inhibitors of host factors—galectins and Hsp90—attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies. IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.Priyanka TyagiVirender Kumar PalRagini AgrawalShalini SinghSandhya SrinivasanAmit SinghAmerican Society for Microbiologyarticleglutathioneredox potentialextracellular acidification rateoxidative phosphorylationroGFPMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	glutathione redox potential extracellular acidification rate oxidative phosphorylation roGFP Microbiology QR1-502
spellingShingle	glutathione redox potential extracellular acidification rate oxidative phosphorylation roGFP Microbiology QR1-502 Priyanka Tyagi Virender Kumar Pal Ragini Agrawal Shalini Singh Sandhya Srinivasan Amit Singh <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
description	ABSTRACT The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant—N-acetyl cysteine (NAC)—or with inhibitors of host factors—galectins and Hsp90—attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies. IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.
format	article
author	Priyanka Tyagi Virender Kumar Pal Ragini Agrawal Shalini Singh Sandhya Srinivasan Amit Singh
author_facet	Priyanka Tyagi Virender Kumar Pal Ragini Agrawal Shalini Singh Sandhya Srinivasan Amit Singh
author_sort	Priyanka Tyagi
title	<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
title_short	<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
title_full	<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
title_fullStr	<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
title_full_unstemmed	<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics
title_sort	<named-content content-type="genus-species">mycobacterium tuberculosis</named-content> reactivates hiv-1 via exosome-mediated resetting of cellular redox potential and bioenergetics
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/bb6c30229a30454a9ed868b2b816b07d
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<named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

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