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Agrawal R, Pal VK, K S S, Menon GJ, Singh IR, Malhotra N, C S N, Ganesh K, Rajmani RS, Narain Seshasayee AS, Chandra N, Joshi MB, Singh A. Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. PLoS Pathog 2025; 21:e1013164. [PMID: 40388397 DOI: 10.1371/journal.ppat.1013164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/28/2025] [Indexed: 05/21/2025] Open
Abstract
Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.
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Affiliation(s)
- Ragini Agrawal
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Virender Kumar Pal
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Suhas K S
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Gopika Jayan Menon
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Inder Raj Singh
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Nitish Malhotra
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Naren C S
- Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Kailash Ganesh
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Raju S Rajmani
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Aswin Sai Narain Seshasayee
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, Karnataka, India
| | - Nagasuma Chandra
- Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Manjunath B Joshi
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Udupi, Karnataka, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, Karnataka, India
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Rangaraj S, Agarwal A, Banerjee S. Bird's Eye View on Mycobacterium tuberculosis-HIV Coinfection: Understanding the Molecular Synergism, Challenges, and New Approaches to Therapeutics. ACS Infect Dis 2025; 11:1042-1063. [PMID: 40229972 DOI: 10.1021/acsinfecdis.4c00870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the most common secondary infection in the Human Immunodeficiency Virus (HIV) infected population, accounting for more than one-fourth of deaths in people living with HIV (PLWH). Reciprocally, HIV infection increases the susceptibility to primary TB or reactivation of latent TB by several folds. The synergistic interactions between M.tb and HIV not only potentiate their deleterious impact but also complicate the clinical management of both the diseases. M.tb-HIV coinfected patients have a high risk of failure of accurate diagnosis, treatment inefficiency for both TB and HIV, concurrent nontuberculous mycobacterial infections, other comorbidities such as diabetes mellitus, severe cytotoxicity due to drug overburden, and immune reconstitution inflammatory syndrome (IRIS). The need of the hour is to understand M.tb-HIV coinfection biology and their collective impact on the host immunocompetence and to think of out-of-the-box treatment perspectives, including host-directed therapy under the rising view of homeostatic medicines. This review aims to highlight the molecular players, both from the pathogens and host, that facilitate the synergistic interactions and host-associated proteins/enzymes regulating immunometabolism, underlining potential targets for designing and screening chemical inhibitors to reduce the burden of both pathogens concomitantly during M.tb-HIV coinfection. To appreciate the necessity of revisiting therapeutic approaches and research priorities, we provide a glimpse of anti-TB and antiretroviral drug-drug interactions, project the gaps in our understanding of coinfection biology, and also enlist some key research initiatives that will help us deal with the synergistic epidemic of M.tb-HIV coinfection.
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Affiliation(s)
- Siranjeevi Rangaraj
- Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India
| | - Anushka Agarwal
- Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India
| | - Sharmistha Banerjee
- Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India
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Amegashie EA, Sikeola RO, Tagoe EA, Paintsil E, Torpey K, Quaye O. Oxidative Stress in People Living With HIV: Are Diverse Supplement Sources the Solution? Health Sci Rep 2025; 8:e70824. [PMID: 40330761 PMCID: PMC12054717 DOI: 10.1002/hsr2.70824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/18/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Background and Aim Antiretroviral therapy (ART) has reduced human immunodeficiency virus (HIV)/AIDS to a manageable chronic condition even though no cure exists. Despite ART control, latent HIV infection results in failed memory CD4 T-cell responses, immune overactivation, inflammation, oxidative stress, genomic instability, deoxyribonucleic acid (DNA) damage, and premature CD4 T-cell ageing. Overproduction of reactive oxygen species during oxidative stress can cause mitochondrial DNA damage, cancer, neurodegenerative and cardiovascular diseases, and premature aging in people living with HIV (PLWH). This review outlines current knowledge in oxidative stress among PLWH. Methods Google Scholar, Scopus, PubMed, and Science Direct were searched for literature conforming with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines from studies published from January 2013 to December 2023. A total of 75 studies from 22 countries were identified, with 52 studies carried out in human participants, 17 studies in cell lines, and 6 studies in animal models to assess oxidative stress levels. Results An increased oxidative stress with no changes in antioxidant levels was reported in HIV-positive smokers, and those on substance abuse. Long-term ART usage showed high levels of oxidative protein products and low levels of antioxidants when compared to short-term ART usage. The use of supplements such as N-acetylcysteine, selenium, and silibinin in animal models and cell lines showed increased cell viability, reduced reactive oxygen species, and increased antioxidant levels, which are promising therapeutic interventions that should be studied in PLWH to further help improve their disease outcomes. Conclusions Identifying extracts from natural and synthetic products with antioxidant effects will improve the general well-being of PLWH.
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Affiliation(s)
- Esimebia Adjovi Amegashie
- West African Center for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular BiologyUniversity of GhanaAccraGreater Accra RegionGhana
| | - Ruth Oyawole Sikeola
- West African Center for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular BiologyUniversity of GhanaAccraGreater Accra RegionGhana
| | - Emmanuel Ayitey Tagoe
- Department of Medical Laboratory SciencesSchool of Biomedical and Allied Health Sciences, University of GhanaAccraGreater Accra RegionGhana
| | - Elijah Paintsil
- Department of PediatricsBoston University Chobanian & Avedisian School of MedicineBostonUSA
| | - Kwasi Torpey
- Department of Population, Family and Reproductive HealthSchool of Public Health, University of GhanaAccraGreater Accra RegionGhana
| | - Osbourne Quaye
- West African Center for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular BiologyUniversity of GhanaAccraGreater Accra RegionGhana
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Manna S, Agrawal R, Yadav T, Kumar TA, Kumari P, Dalai A, Kanade S, Balasubramanian N, Singh A, Chakrapani H. Orthogonal Persulfide Generation through Precision Tools Provides Insights into Mitochondrial Sulfane Sulfur. Angew Chem Int Ed Engl 2024; 63:e202411133. [PMID: 39091222 DOI: 10.1002/anie.202411133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/24/2024] [Accepted: 08/01/2024] [Indexed: 08/04/2024]
Abstract
The sulfane sulfur pool, comprised of persulfide (RS-SH) and polysulfide (RS-SnH) derived from hydrogen sulfide (H2S), has emerged as a major player in redox biochemistry. Mitochondria, besides energy generation, serve as significant cellular redox hubs, mediate stress response and cellular health. However, the effects of endogenous mitochondrial sulfane sulfur (MSS) remain largely uncharacterized as compared with their cytosolic counterparts, cytosolic sulfane sulfur (CSS). To investigate this, we designed a novel artificial substrate for mitochondrial 3-mercaptopyruvate sulfurtransferase (3-MST), a key enzyme involved in MSS biosynthesis. Using cells expressing a mitochondrion-localized persulfide biosensor, we demonstrate this tool's ability to selectively enhance MSS. While H2S was previously known to suppress human immunodeficiency virus (HIV-1), we found that MSS profoundly affected the HIV-1 life cycle, mediating viral reactivation from latency. Additionally, we provide evidence for the role of the host's mitochondrial redox state, membrane potential, apoptosis, and respiration rates in managing HIV-1 latency and reactivation. Together, dynamic fluctuations in the MSS pool have a significant and possibly conflicting effect on HIV-1 viral latency. The precision tools developed herein allow for orthogonal generation of persulfide within both mitochondria and the cytosol and will be useful in interrogating disease biology.
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Affiliation(s)
- Suman Manna
- Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Ragini Agrawal
- Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Tarun Yadav
- Department of Biology, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - T Anand Kumar
- Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Pooja Kumari
- Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Aadishakti Dalai
- Department of Biology, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Shaunak Kanade
- Department of Biology, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Nagaraj Balasubramanian
- Department of Biology, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Harinath Chakrapani
- Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India
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Cronin S, de Vries-Egan A, Vahlas Z, Czernikier A, Melucci C, Pereyra Gerber P, O’Neil T, Gloss B, Sharabas M, Turk G, Verollet C, Balboa L, Palmer S, Duette G. The immunosuppressive tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4 + T cells. iScience 2024; 27:110324. [PMID: 39055929 PMCID: PMC11269811 DOI: 10.1016/j.isci.2024.110324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/15/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied. Using the acellular fraction of tuberculous pleural effusion (TB-PE), we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Our results revealed that TB-PE impaired T cell receptor-dependent cell activation and decreased HIV-1 replication in CD4+ T cells. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation. This study indicates that the TB-induced immune response may contribute to the persistence of the viral reservoir by silencing HIV-1 expression, allowing the virus to persist undetected by the immune system, and increasing the size of the latent HIV-1 reservoir.
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Affiliation(s)
- Samantha Cronin
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Anneke de Vries-Egan
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Zoï Vahlas
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, Centre National de La Recherche Scientifique, Université Toulouse III - Paul Sabatier (UPS), 31077 Toulouse, France
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
| | - Alejandro Czernikier
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Claudia Melucci
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Pehuén Pereyra Gerber
- Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK
| | - Thomas O’Neil
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Brian Gloss
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Mayssa Sharabas
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Gabriela Turk
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Christel Verollet
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, Centre National de La Recherche Scientifique, Université Toulouse III - Paul Sabatier (UPS), 31077 Toulouse, France
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
| | - Luciana Balboa
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
- Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Buenos Aires C1425ASU, Argentina
| | - Sarah Palmer
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Gabriel Duette
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
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6
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Espejo C, Ezenwa VO. Extracellular vesicles: an emerging tool for wild immunology. DISCOVERY IMMUNOLOGY 2024; 3:kyae011. [PMID: 39005930 PMCID: PMC11244269 DOI: 10.1093/discim/kyae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/12/2024] [Accepted: 06/23/2024] [Indexed: 07/16/2024]
Abstract
The immune system is crucial for defending organisms against pathogens and maintaining health. Traditionally, research in immunology has relied on laboratory animals to understand how the immune system works. However, there is increasing recognition that wild animals, due to their greater genetic diversity, lifespan, and environmental exposures, have much to contribute to basic and translational immunology. Unfortunately, logistical challenges associated with collecting and storing samples from wildlife, and the lack of commercially available species-specific reagents have hindered the advancement of immunological research on wild species. Extracellular vesicles (EVs) are cell-derived nanoparticles present in all body fluids and tissues of organisms spanning from bacteria to mammals. Human and lab animal studies indicate that EVs are involved in a range of immunological processes, and recent work shows that EVs may play similar roles in diverse wildlife species. Thus, EVs can expand the toolbox available for wild immunology research, helping to overcome some of the challenges associated with this work. In this paper, we explore the potential application of EVs to wild immunology. First, we review current understanding of EV biology across diverse organisms. Next, we discuss key insights into the immune system gained from research on EVs in human and laboratory animal models and highlight emerging evidence from wild species. Finally, we identify research themes in wild immunology that can immediately benefit from the study of EVs and describe practical considerations for using EVs in wildlife research.
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Affiliation(s)
- Camila Espejo
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
| | - Vanessa O Ezenwa
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
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7
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Sun X, Li W, Zhao L, Fan K, Qin F, Shi L, Gao F, Zheng C. Current landscape of exosomes in tuberculosis development, diagnosis, and treatment applications. Front Immunol 2024; 15:1401867. [PMID: 38846947 PMCID: PMC11153741 DOI: 10.3389/fimmu.2024.1401867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 05/09/2024] [Indexed: 06/09/2024] Open
Abstract
Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (MTB), remains one of the most prevalent and deadly infectious diseases worldwide. Currently, there are complex interactions between host cells and pathogens in TB. The onset, progression, and regression of TB are correlated not only with the virulence of MTB but also with the immunity of TB patients. Exosomes are cell-secreted membrane-bound nanovesicles with lipid bilayers that contain a variety of biomolecules, such as metabolites, lipids, proteins, and nucleic acids. Exosome-mediated cell-cell communication and interactions with the microenvironment represent crucial mechanisms through which exosomes exert their functional effects. Exosomes harbor a wide range of regulatory roles in physiological and pathological conditions, including MTB infection. Exosomes can regulate the immune response, metabolism, and cellular death to remodel the progression of MTB infection. During MTB infection, exosomes display distinctive profiles and quantities that may act as diagnostic biomarkers, suggesting that exosomes provide a revealing glimpse into the evolving landscape of MTB infections. Furthermore, exosomes derived from MTB and mesenchymal stem cells can be harnessed as vaccine platforms and drug delivery vehicles for the precise targeting and treatment of TB. In this review, we highlight the functions and mechanisms through which exosomes influence the progression of TB. Additionally, we unravel the critical significance of exosomal constituents in the diagnosis and therapeutic applications of TB, aiming to offer novel perspectives and strategies for combating TB.
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Affiliation(s)
- Xuezhi Sun
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Wei Li
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Li Zhao
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Ke Fan
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Fenfen Qin
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Liwen Shi
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Feng Gao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunlan Zheng
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
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8
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Zhang L, Cai M, Su B, Ma Y, Zhang Y. Mitochondrial Metabolism in Alveolar Macrophages of Patients Infected with HIV, Tuberculosis, and HIV/Tuberculosis. AIDS Res Hum Retroviruses 2024; 40:148-157. [PMID: 37885217 DOI: 10.1089/aid.2023.0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023] Open
Abstract
Tuberculosis (TB) is one of the most common opportunistic infections and is a leading cause of mortality in patients with HIV and AIDS. HIV infection causes serious defects in the host immune system and increases the risk of active TB. TB infection promotes HIV replication and aggravates host damage in patients with HIV/AIDS. Alveolar macrophages (AMs) are essential immune cells during TB and HIV infections. AMs undergo a shift in mitochondrial metabolism during TB or HIV infection, that is, metabolic reprogramming, allowing them to act in the form of classical activated macrophages (M1) and alternative activated macrophages (M2) at different stages of infection. We reviewed the alterations in the mitochondrial energy metabolism of AMs in patients with HIV, TB, and HIV/TB to provide ideas for further research on the role of metabolic reprogramming by AMs in the pathogeneses of HIV, TB, and HIV/TB coinfection.
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Affiliation(s)
- Ling Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Miaotian Cai
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yingmin Ma
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yulin Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
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9
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Konas D, Cho S, Thomas OD, Bhatti MM, Leon Hernandez K, Moran C, Booter H, Candela T, Lacap J, McFadden P, van den Berg S, Welter AM, Peralta A, Janson CA, Catalano J, Goodey NM. Investigating the Roles of Active Site Residues in Mycobacterium tuberculosis Indole-3-glycerol Phosphate Synthase, a Potential Target for Antitubercular Agents. ACS BIO & MED CHEM AU 2023; 3:438-447. [PMID: 37876495 PMCID: PMC10591298 DOI: 10.1021/acsbiomedchemau.3c00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 10/26/2023]
Abstract
Mycobacterium tuberculosis drug resistance is emerging and new drug targets are needed. Tryptophan biosynthesis is necessary for M. tuberculosis replication and virulence. Indole-3-glycerol phosphate synthase (IGPS) catalyzes a step in M. tuberculosis tryptophan biosynthesis and has been suggested as a potential anti-infective target, but our understanding of this enzyme is limited. To aid in inhibitor design and gain a greater mechanistic picture of this enzyme, there is a need to understand the roles of active site amino acids in ligand binding and catalysis. In this work, we explored the roles of conserved active site amino acids Glu57, Lys59, Lys119, Glu168, and Glu219. Mutation of each to Ala results in loss of all detectable activity. The Glu57Gln, Lys59Arg, Lys119Arg, Glu168Gln, and Glu219Asp mutations result in large activity losses, while Glu219Gln has enhanced activity. Analysis of the enzymatic data yields the following main conclusions: (A) Lys119 is the likely catalytic acid in the CdRP ring closure step. (B) Glu168 stabilizes a charged reaction intermediate and may also be the catalytic base. (C) Glu57, Glu219, and Lys119 form a closely arranged triad in which Glu57 and Glu219 modulate the pKa of Lys119, and thus overall activity. This increased understanding of inter- and intramolecular interactions and demonstration of the highly coordinated nature of the M. tuberculosis IGPS active site provide new mechanistic information and guidance for future work with this potential new drug target.
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Affiliation(s)
- David
W. Konas
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Sarah Cho
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Oshane D. Thomas
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Maryum M. Bhatti
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Katherine Leon Hernandez
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Cinthya Moran
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Hedda Booter
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Thomas Candela
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Joseph Lacap
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Paige McFadden
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Savannah van den Berg
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Alyssa M. Welter
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Ashley Peralta
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Cheryl A. Janson
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Jaclyn Catalano
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
| | - Nina M. Goodey
- Department of Chemistry and
Biochemistry, Montclair State University 1 Normal Avenue, Montclair, New Jersey 07043, United States
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10
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Wen L, Shi L, Wan SS, Xu T, Zhang L, Zhou ZG. Changes in the balance of Th17/Treg cells and oxidative stress markers in patients with HIV‑associated pulmonary tuberculosis who develop IRIS. Exp Ther Med 2023; 25:271. [PMID: 37206552 PMCID: PMC10189753 DOI: 10.3892/etm.2023.11970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 02/23/2023] [Indexed: 05/21/2023] Open
Abstract
Tuberculosis (TB) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection and is one of the primary causes of death from AIDS. The increased accessibility to highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of patients with HIV infection. However, following ART, rapid restoration of the immune system leads to immune reconstitution inflammatory syndrome (IRIS). Oxidative stress and innate immunity play a role in TB-associated IRIS (TB-IRIS). The present study investigated the changes that occur in oxidative stress markers and T helper (Th)17/regulatory T (Treg) cell balance and their significance in IRIS patients with HIV-associated pulmonary TB. A total of 316 patients with HIV-associated pulmonary TB were treated with HAART and followed up regularly for 12 weeks. Those who developed IRIS were included in the IRIS group (n=60), while the remaining patients were included in the non-IRIS group (n=256). The changes in plasma oxidative stress markers superoxide dismutase (SOD) and malondialdehyde (MDA) were detected with the ELISA, and the ratio of Th17 to Treg cells in whole blood were analyzed before and after treatment through the flow cytometric assay. Following treatment, MDA and Th17 cells levels were significantly increased while SOD and Treg cells levels were decreased in the IRIS group (P<0.05) compared with before treatment. In the non-IRIS group, a non-significant decrease was observed in SOD levels (P>0.05), while the MDA levels significantly decreased compared with before treatment (P<0.05) and the Th17 and Treg cells levels were both significantly increased (P<0.05). After treatment, compared with the non-IRIS group, the IRIS group showed a significant increase in MDA and Th17 cells and decrease in SOD and Treg cells levels (P<0.05). In addition, Th17 cells levels were positively correlated with MDA but negatively correlated with SOD levels. Treg levels were negatively correlated with MDA and positively correlated with SOD levels (P<0.05). The area under the curve values of serum MDA and SOD, Th17 and Treg levels predicting the occurrence of IRIS were 0.738, 0.883, 0.722 and 0.719, respectively (P<0.05). These results indicated that the above parameters have certain diagnostic value for the occurrence of IRIS. The occurrence of IRIS in patients with HIV-associated pulmonary TB may be associated with oxidative stress and Th17/Treg cell imbalance.
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Affiliation(s)
- Long Wen
- Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, Changsha, Hunan 410000, P.R. China
| | - Lei Shi
- Department of Nursing, The Fourth Hospital of Changsha, Changsha, Hunan 410000, P.R. China
| | - Shan-Shan Wan
- Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, Changsha, Hunan 410000, P.R. China
| | - Tao Xu
- Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, Changsha, Hunan 410000, P.R. China
| | - Lei Zhang
- Department of Respiratory Medicine, Yicheng People's Hospital of Shandong, Zaozhuang, Shandong 277300, P.R. China
- Correspondence to: Dr Zhi-Guo Zhou, Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, 311 Yingpan Road, Kaifu, Changsha, Hunan 410000, P.R. China
| | - Zhi-Guo Zhou
- Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, Changsha, Hunan 410000, P.R. China
- Correspondence to: Dr Zhi-Guo Zhou, Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, The First Hospital of Changsha, 311 Yingpan Road, Kaifu, Changsha, Hunan 410000, P.R. China
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11
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Sau S, Roy A, Agnivesh PK, Kumar S, Guru SK, Sharma S, Kalia NP. Unravelling the flexibility of Mycobacterium tuberculosis: an escape way for the bacilli. J Med Microbiol 2023; 72. [PMID: 37261969 DOI: 10.1099/jmm.0.001695] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
The persistence of Mycobacterium tuberculosis makes it difficult to eradicate the associated infection from the host. The flexible nature of mycobacteria and their ability to adapt to adverse host conditions give rise to different drug-tolerant phenotypes. Granuloma formation restricts nutrient supply, limits oxygen availability and exposes bacteria to a low pH environment, resulting in non-replicating bacteria. These non-replicating mycobacteria, which need high doses and long exposure to anti-tubercular drugs, are the root cause of lengthy chemotherapy. Novel strategies, which are effective against non-replicating mycobacteria, need to be adopted to shorten tuberculosis treatment. This not only will reduce the treatment time but also will help prevent the emergence of multi-drug-resistant strains of mycobacteria.
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Affiliation(s)
- Shashikanta Sau
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Arnab Roy
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Puja Kumari Agnivesh
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Sunil Kumar
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Santosh Kumar Guru
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Sandeep Sharma
- Department of Medical Laboratory Sciences, Lovely Professional University, Phagwara, Punjab -144411, India
| | - Nitin Pal Kalia
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
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12
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Ghelichkhani F, Gonzalez FA, Kapitonova MA, Schaefer-Ramadan S, Liu J, Cheng R, Rozovsky S. Selenoprotein S: A versatile disordered protein. Arch Biochem Biophys 2022; 731:109427. [PMID: 36241082 PMCID: PMC10026367 DOI: 10.1016/j.abb.2022.109427] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/16/2022]
Abstract
Selenoprotein S (selenos) is a small, intrinsically disordered membrane protein that is associated with various cellular functions, such as inflammatory processes, cellular stress response, protein quality control, and signaling pathways. It is primarily known for its contribution to the ER-associated degradation (ERAD) pathway, which governs the extraction of misfolded proteins or misassembled protein complexes from the ER to the cytosol for degradation by the proteasome. However, selenos's other cellular roles in signaling are equally vital, including the control of transcription factors and cytokine levels. Consequently, genetic polymorphisms of selenos are associated with increased risk for diabetes, dyslipidemia, and cardiovascular diseases, while high expression levels correlate with poor prognosis in several cancers. Its inhibitory role in cytokine secretion is also exploited by viruses. Since selenos binds multiple protein complexes, however, its specific contributions to various cellular pathways and diseases have been difficult to establish. Thus, the precise cellular functions of selenos and their interconnectivity have only recently begun to emerge. This review aims to summarize recent insights into the structure, interactome, and cellular roles of selenos.
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Affiliation(s)
- Farid Ghelichkhani
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA
| | - Fabio A Gonzalez
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA
| | - Mariia A Kapitonova
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA
| | | | - Jun Liu
- Enlaza Therapeutics, 11099 N. Torrey Pines Rd, suite 290, La Jolla, CA, 92037, USA
| | - Rujin Cheng
- NGM Biopharmaceuticals, Inc., 333 Oyster Point Blvd, South San Francisco, CA, 94080, USA
| | - Sharon Rozovsky
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
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13
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Liebenberg D, Gordhan BG, Kana BD. Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management. Front Cell Infect Microbiol 2022; 12:943545. [PMID: 36211964 PMCID: PMC9538507 DOI: 10.3389/fcimb.2022.943545] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/06/2022] [Indexed: 01/17/2023] Open
Abstract
Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.
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14
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Esposito N, Konas DW, Goodey NM. Indole-3-Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target. Chembiochem 2022; 23:e202100314. [PMID: 34383995 PMCID: PMC9041893 DOI: 10.1002/cbic.202100314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/29/2021] [Indexed: 01/21/2023]
Abstract
Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, affects millions of people worldwide. Several TB drugs have lost efficacy due to emerging drug resistance and new anti-TB targets are needed. Recent research suggests that indole-3-glycerol phosphate synthase (IGPS) in M. tuberculosis (MtIGPS) could be such a target. IGPS is a (β/α)8 -barrel enzyme that catalyzes the conversion of 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate (CdRP) into indole-glycerol-phosphate (IGP) in the bacterial tryptophan biosynthetic pathway. M. tuberculosis over expresses the tryptophan pathway genes during an immune response and inhibition of MtIGPS allows CD4 T-cells to more effectively fight against M. tuberculosis. Here we review the published data on MtIGPS expression, kinetics, mechanism, and inhibition. We also discuss MtIGPS crystal structures and compare them to other IGPS structures to reveal potential structure-function relationships of interest for the purposes of drug design and biocatalyst engineering.
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Affiliation(s)
- Nikolas Esposito
- Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ, 07043, USA
| | - David W. Konas
- Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ, 07043, USA
| | - Nina M. Goodey
- Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ, 07043, USA
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15
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Pshennikova ES, Voronina AS. Dormancy: There and Back Again. Mol Biol 2022; 56:735-755. [PMID: 36217335 PMCID: PMC9534470 DOI: 10.1134/s0026893322050119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/27/2022] [Accepted: 03/27/2022] [Indexed: 11/04/2022]
Abstract
Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body. These cells are resistant to therapy that can destroy intensely dividing cells and to the host immune system. A cascade of reactions that allows cells to enter and exit dormancy is triggered by regulatory factors from the microenvironment in niches that harbor the cells. A ratio of forbidding and permitting signals dictates whether the cells become dormant or start proliferation. The only difference between the cell dormancy regulation in normal and pathological conditions is that pathogens, mycobacteria, and cancer cells can influence their own fate by changing their microenvironment. Certain mechanisms of these processes are considered in the review.
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Affiliation(s)
- E. S. Pshennikova
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
| | - A. S. Voronina
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
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16
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Pal VK, Agrawal R, Rakshit S, Shekar P, Murthy DTN, Vyakarnam A, Singh A. Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis. eLife 2021; 10:68487. [PMID: 34792020 PMCID: PMC8660018 DOI: 10.7554/elife.68487] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 11/17/2021] [Indexed: 01/12/2023] Open
Abstract
A fundamental challenge in human immunodeficiency virus (HIV) eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H2S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H2S producing enzyme cystathionine-γ-lyase (CTH) and reduction in endogenous H2S. Genetic silencing of CTH disrupts redox homeostasis, impairs mitochondrial function, and remodels the transcriptome of latent cells to trigger HIV reactivation. Chemical complementation of CTH activity using a slow-releasing H2S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-κB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4+ T cells from ART-suppressed human subjects, GYY4137 in combination with ART prevented viral rebound and improved mitochondrial bioenergetics. Moreover, prolonged exposure to GYY4137 exhibited no adverse influence on proviral content or CD4+ T cell subsets, indicating that diminished viral rebound is due to a loss of transcription rather than a selective loss of infected cells. In summary, this work provides mechanistic insight into H2S-mediated suppression of viral rebound and suggests exploration of H2S donors to maintain HIV in a latent form.
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Affiliation(s)
- Virender Kumar Pal
- Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Ragini Agrawal
- Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | | | - Pooja Shekar
- BMCRI, Bangalore Medical College and Research Institute, Bangalore, India
| | | | | | - Amit Singh
- Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
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17
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Devi P, Khan A, Chattopadhyay P, Mehta P, Sahni S, Sharma S, Pandey R. Co-infections as Modulators of Disease Outcome: Minor Players or Major Players? Front Microbiol 2021; 12:664386. [PMID: 34295314 PMCID: PMC8290219 DOI: 10.3389/fmicb.2021.664386] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.
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Affiliation(s)
- Priti Devi
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Azka Khan
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Partha Chattopadhyay
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Priyanka Mehta
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Shweta Sahni
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sachin Sharma
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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18
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Mishra R, Yadav V, Guha M, Singh A. Heterogeneous Host-Pathogen Encounters Coordinate Antibiotic Resilience in Mycobacterium tuberculosis. Trends Microbiol 2021; 29:606-620. [PMID: 33309526 PMCID: PMC7611257 DOI: 10.1016/j.tim.2020.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/25/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022]
Abstract
Successful treatment of tuberculosis (TB) depends on the eradication of its causative agent Mycobacterium tuberculosis (Mtb) in the host. However, the emergence of phenotypically drug-resistant Mtb in the host environment tempers the ability of antibiotics to cure disease. Host immunity produces diverse microenvironmental niches that are exploited by Mtb to mobilize adaptation programs. Such differential interactions amplify pre-existing heterogeneity in the host-pathogen milieu to influence disease pathology and therapy outcome. Therefore, comprehending the intricacies of phenotypic heterogeneity can be an empirical step forward in potentiating drug action. With this goal, we review the interconnectedness of the lesional, cellular, and bacterial heterogeneity underlying phenotypic drug resistance. Based on this information, we anticipate the development of new therapeutic strategies targeting host-pathogen heterogeneity to cure TB.
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Affiliation(s)
- Richa Mishra
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru-560012, India; Centre for Infectious Disease and Research (CIDR), Indian Institute of Science, Bengaluru-560012, India
| | - Vikas Yadav
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru-560012, India; Centre for Infectious Disease and Research (CIDR), Indian Institute of Science, Bengaluru-560012, India
| | - Madhura Guha
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru-560012, India; Centre for Infectious Disease and Research (CIDR), Indian Institute of Science, Bengaluru-560012, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru-560012, India; Centre for Infectious Disease and Research (CIDR), Indian Institute of Science, Bengaluru-560012, India.
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19
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Sivaji N, Harish N, Singh S, Singh A, Vijayan M, Surolia A. Mevo lectin specificity towards high-mannose structures with terminal αMan(1,2)αMan residues and its implication to inhibition of the entry of Mycobacterium tuberculosis into macrophages. Glycobiology 2021; 31:1046-1059. [PMID: 33822039 DOI: 10.1093/glycob/cwab022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/20/2022] Open
Abstract
Mannose-binding lectins can specifically recognize and bind complex glycan structures on pathogens and have potential as anti-viral and anti-bacterial agents. We previously reported the structure of a lectin from an archaeal species, Mevo lectin, which has specificity towards terminal α1,2 linked manno-oligosaccharides. Mycobacterium tuberculosis (M. tuberculosis) expresses mannosylated structures including, lipoarabinomannan (ManLAM) on its surface and exploits C-type lectins to gain entry into the host cells. ManLAM structure has mannose capping with terminal αMan(1,2)αMan residues and is important for recognition by innate immune cells. Here, we aim to address the specificity of Mevo lectin towards high-mannose type glycans with terminal αMan(1,2)αMan residues and its effect on M. tuberculosis internalization by macrophages. ITC studies demonstrated that Mevo lectin shows preferential binding towards manno-oligosaccharides with terminal αMan(1,2)αMan structures, and showed a strong affinity for ManLAM, whereas it binds weakly to Mycobacterium smegmatis (M. smegmatis) lipoarabinomannan (MsmLAM), which displays relatively fewer and shorter mannosyl caps. Crystal structure of Mevo lectin complexed with a Man7D1 revealed the multivalent cross-linking interaction, which explains avidity-based high affinity for these ligands when compared to previously studied manno-oligosaccharides lacking the specific termini. Functional studies suggest that M. tuberculosis internalization by the macrophage was impaired by binding of Mevo lectin to ManLAM present on the surface of M. tuberculosis. Selectivity shown by Mevo lectin towards glycans with terminal αMan(1,2)αMan structures, and its ability to compromise the internalization of M. tuberculosis in vitro, underscore the potential utility of Mevo lectin as a research tool to study host-pathogen interactions.
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Affiliation(s)
- Nukathoti Sivaji
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
| | - Nikitha Harish
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
| | - Samsher Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | - Mamannamana Vijayan
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
| | - Avadhesha Surolia
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
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20
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Singh S, Ghosh S, Pal VK, Munshi M, Shekar P, Narasimha Murthy DT, Mugesh G, Singh A. Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential. EMBO Mol Med 2021; 13:e13314. [PMID: 33793064 PMCID: PMC8103102 DOI: 10.15252/emmm.202013314] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/05/2021] [Accepted: 02/19/2021] [Indexed: 12/23/2022] Open
Abstract
Reactive oxygen species (ROS) regulates the replication of human immunodeficiency virus (HIV‐1) during infection. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to the harmful consequences of manipulating cellular antioxidant systems. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic natural glutathione peroxidase activity to mitigate ROS associated with HIV‐1 infection without adversely affecting cellular physiology. Using genetic reporters of glutathione redox potential and hydrogen peroxide, we showed that V2O5 nanosheets catalyze ROS neutralization in HIV‐1‐infected cells and uniformly block viral reactivation and replication. Mechanistically, V2O5 nanosheets suppressed HIV‐1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g., NF‐κB), inflammation, and apoptosis. Importantly, a combination of V2O5 nanosheets with a pharmacological inhibitor of NF‐κB (BAY11‐7082) abrogated reactivation of HIV‐1. Lastly, V2O5 nanosheets inhibit viral reactivation upon prostratin stimulation of latently infected CD4+ T cells from HIV‐infected patients receiving suppressive antiretroviral therapy. Our data successfully revealed the usefulness of V2O5 nanosheets against HIV and suggested nanozymes as future platforms to develop interventions against infectious diseases.
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Affiliation(s)
- Shalini Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.,Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India
| | - Sourav Ghosh
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India
| | - Virender Kumar Pal
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.,Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India
| | - MohamedHusen Munshi
- Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India
| | - Pooja Shekar
- Bangalore Medical College and Research Institute, Bangalore, India
| | | | - Govindasamy Mugesh
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.,Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India
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21
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Vinhaes CL, Araujo-Pereira M, Tibúrcio R, Cubillos-Angulo JM, Demitto FO, Akrami KM, Andrade BB. Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV. Life (Basel) 2021; 11:life11010065. [PMID: 33477581 PMCID: PMC7831327 DOI: 10.3390/life11010065] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/19/2022] Open
Abstract
Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.
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Affiliation(s)
- Caian L. Vinhaes
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, Salvador 40290-000, Brazil
| | - Mariana Araujo-Pereira
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Rafael Tibúrcio
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Juan M. Cubillos-Angulo
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Fernanda O. Demitto
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
| | - Kevan M. Akrami
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
- Divisions of Infectious Diseases and Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Bruno B. Andrade
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, Salvador 40290-000, Brazil
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
- Curso de Medicina, Centro Universitário Faculdade de Tecnologia e Ciências (UniFTC), Salvador 41741-590, Brazil
- Correspondence: ; Tel.: +55-71-3176-2264
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22
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Biadglegne F, König B, Rodloff AC, Dorhoi A, Sack U. Composition and Clinical Significance of Exosomes in Tuberculosis: A Systematic Literature Review. J Clin Med 2021; 10:E145. [PMID: 33406750 PMCID: PMC7795701 DOI: 10.3390/jcm10010145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/21/2022] Open
Abstract
Tuberculosis (TB) remains a major health issue worldwide. In order to contain TB infections, improved vaccines as well as accurate and reliable diagnostic tools are desirable. Exosomes are employed for the diagnosis of various diseases. At present, research on exosomes in TB is still at the preliminary stage. Recent studies have described isolation and characterization of Mycobacterium tuberculosis (Mtb) derived exosomes in vivo and in vitro. Mtb-derived exosomes (Mtbexo) may be critical for TB pathogenesis by delivering mycobacterial-derived components to the recipient cells. Proteomic and transcriptomic analysis of Mtbexo have revealed a variety of proteins and miRNA, which are utilized by the TB bacteria for pathogenesis. Exosomes has been isolated in body fluids, are amenable for fast detection, and could contribute as diagnostic or prognostic biomarker to disease control. Extraction of exosomes from biological fluids is essential for the exosome research and requires careful standardization for TB. In this review, we summarized the different studies on Mtbexo molecules, including protein and miRNA and the method used to detect exosomes in biological fluids and cell culture supernatants. Thus, the detection of Mtbexo molecules in biological fluids may have a potential to expedite the diagnosis of TB infection. Moreover, the analysis of Mtbexo may generate new aspects in vaccine development.
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Affiliation(s)
- Fantahun Biadglegne
- College of Medicine and Health Sciences, Bahir Dar University, 79 Bahir Dar, Ethiopia
- Institute of Medical Microbiology and Epidemiology of Infectious Diseases, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; (B.K.); (A.C.R.)
- Institute of Clinical Immunology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany;
| | - Brigitte König
- Institute of Medical Microbiology and Epidemiology of Infectious Diseases, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; (B.K.); (A.C.R.)
| | - Arne C. Rodloff
- Institute of Medical Microbiology and Epidemiology of Infectious Diseases, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; (B.K.); (A.C.R.)
| | - Anca Dorhoi
- Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany;
| | - Ulrich Sack
- Institute of Clinical Immunology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany;
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23
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Auld SC, Staitieh BS. HIV and the tuberculosis "set point": how HIV impairs alveolar macrophage responses to tuberculosis and sets the stage for progressive disease. Retrovirology 2020; 17:32. [PMID: 32967690 PMCID: PMC7509826 DOI: 10.1186/s12977-020-00540-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/15/2020] [Indexed: 11/16/2022] Open
Abstract
As HIV has fueled a global resurgence of tuberculosis over the last several decades, there is a growing awareness that HIV-mediated impairments in both innate and adaptive immunity contribute to the heightened risk of tuberculosis in people with HIV. Since early immune responses to Mycobacterium tuberculosis (Mtb) set the stage for subsequent control or progression to active tuberculosis disease, early host-pathogen interactions following Mtb infection can be thought of as establishing a mycobacterial "set point," which we define as the mycobacterial burden at the point of adaptive immune activation. This early immune response is impaired in the context of HIV coinfection, allowing for a higher mycobacterial set point and greater likelihood of progression to active disease with greater bacterial burden. Alveolar macrophages, as the first cells to encounter Mtb in the lungs, play a critical role in containing Mtb growth and establishing the mycobacterial set point. However, a number of key macrophage functions, ranging from pathogen recognition and uptake to phagocytosis and microbial killing, are blunted in HIV coinfection. To date, research evaluating the effects of HIV on the alveolar macrophage response to Mtb has been relatively limited, particularly with regard to the critical early events that help to dictate the mycobacterial set point. A greater understanding of alveolar macrophage functions impacted by HIV coinfection will improve our understanding of protective immunity to Mtb and may reveal novel pathways amenable to intervention to improve both early immune control of Mtb and clinical outcomes for the millions of people worldwide infected with HIV.
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Affiliation(s)
- Sara C Auld
- Emory University School of Medicine, Atlanta, GA, USA.
- Rollins School of Public Health, Emory University, Atlanta, GA, USA.
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24
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Taunk K, Kalita B, Kale V, Chanukuppa V, Naiya T, Zingde SM, Rapole S. The development and clinical applications of proteomics: an Indian perspective. Expert Rev Proteomics 2020; 17:433-451. [PMID: 32576061 DOI: 10.1080/14789450.2020.1787157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Proteomic research has been extensively used to identify potential biomarkers or targets for various diseases. Advances in mass spectrometry along with data analytics have led proteomics to become a powerful tool for exploring the critical molecular players associated with diseases, thereby, playing a significant role in the development of proteomic applications for the clinic. AREAS COVERED This review presents recent advances in the development and clinical applications of proteomics in India toward understanding various diseases including cancer, metabolic diseases, and reproductive diseases. Keywords combined with 'clinical proteomics in India' 'proteomic research in India' and 'mass spectrometry' were used to search PubMed. EXPERT OPINION The past decade has seen a significant increase in research in clinical proteomics in India. This approach has resulted in the development of proteomics-based marker technologies for disease management in the country. The majority of these investigations are still in the discovery phase and efforts have to be made to address the intended clinical use so that the identified potential biomarkers reach the clinic. To move toward this necessity, there is a pressing need to establish some key infrastructure requirements and meaningful collaborations between the clinicians and scientists which will enable more effective solutions to address health issues specific to India.
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Affiliation(s)
- Khushman Taunk
- Proteomics Lab, National Centre for Cell Science , Pune, Maharashtra, India.,Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, West Bengal , Haringhata, West Bengal, India
| | - Bhargab Kalita
- Proteomics Lab, National Centre for Cell Science , Pune, Maharashtra, India
| | - Vaikhari Kale
- Proteomics Lab, National Centre for Cell Science , Pune, Maharashtra, India
| | | | - Tufan Naiya
- Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, West Bengal , Haringhata, West Bengal, India
| | - Surekha M Zingde
- CH3-53, Kendriya Vihar, Sector 11, Kharghar , Navi Mumbai, Maharashtra, India
| | - Srikanth Rapole
- Proteomics Lab, National Centre for Cell Science , Pune, Maharashtra, India
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25
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Howard NC, Khader SA. Immunometabolism during Mycobacterium tuberculosis Infection. Trends Microbiol 2020; 28:832-850. [PMID: 32409147 DOI: 10.1016/j.tim.2020.04.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 12/26/2022]
Abstract
Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.
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Affiliation(s)
- Nicole C Howard
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Shabaana A Khader
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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