Tyagi, P and Pal, VK and Agrawal, R and Singh, S and Srinivasan, S and Singh, A (2020) Mycobacterium tuberculosis reactivates hiv-1 via exosome-mediated resetting of cellular redox potential and bioenergetics. In: mBio, 11 (2).
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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�ga-lectins and Hsp90 �attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bio-energetics 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. © 2020 Tyagi et al.
| Item Type: | Journal Article |
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| Publication: | mBio |
| Publisher: | AMER SOC MICROBIOLOGY |
| Additional Information: | The copyright of this article belongs to AMER SOC MICROBIOLOGY |
| Keywords: | acetylcysteine; galectin; heat shock protein 90; hypoxia inducible factor 1alpha; protein inhibitor, aminoglycoside resistance; animal cell; Article; bacterial strain; bioenergy; cellular secretion; coculture; controlled study; exosome; gene expression; host; human; human cell; Human immunodeficiency virus 1; inflammation; macrophage; mitochondrion; mixed infection; mouse; Mycobacterium tuberculosis; nonhuman; oxidation reduction reaction; oxidative stress; oxygen consumption; priority journal; proteomics; reverse transcription polymerase chain reaction; transmission electron microscopy; virus activation; virus reactivation; Western blotting |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research |
| Date Deposited: | 26 Jun 2020 10:32 |
| Last Modified: | 26 Jun 2020 10:32 |
| URI: | http://eprints.iisc.ac.in/id/eprint/64867 |
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