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1
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Viswanathan G, Hughes EJ, Gan M, Xet-Mull AM, Alexander G, Swain-Lenz D, Liu Q, Tobin DM. Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.26.650783. [PMID: 40391323 PMCID: PMC12087985 DOI: 10.1101/2025.04.26.650783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive in nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA-seq across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Through pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through upregulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K + transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection. Summary sentence Dual host-pathogen transcriptional profiling defines granuloma-specific programs during mycobacterial infection.
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2
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Jiang Q, Kumar R, Zhao Y, Subbian S, Shi L. Arginine as host directed therapy in tuberculosis: insights from modulating arginine metabolism by supplementation and arginase inhibition. ONE HEALTH ADVANCES 2025; 3:5. [PMID: 40124736 PMCID: PMC11928424 DOI: 10.1186/s44280-025-00070-6] [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: 12/30/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge. Arginine metabolism is central to immune responses, regulating nitric oxide (NO) production via inducible NO synthase (Nos2) and competing pathways mediated by arginases (Arg1 and Arg2). This study examines the impact of arginine supplementation and arginase inhibition during the acute phase of Mtb infection in mouse lungs, focusing on immune function, lung pathology, and mitochondrial function. Arginine supplementation enhanced Nos2 expression, promoted mitophagy, and supported angiogenesis and/or tissue repair by upregulating Vegfa. These mechanisms synergized to balance pro-inflammatory responses with tissue repair, improving immune defense while mitigating lung damage. In contrast, arginase inhibition disrupted Vegfa-mediated immune homeostasis, and impaired mitophagy, leading to exacerbated lung pathology. These findings underscore the complementary roles of Nos2 and arginase-mediated pathways in maintaining immune equilibrium during Mtb infection. Our results highlight arginine supplementation as a promising host-directed therapy for TB, capable of enhancing protective immunity and facilitating tissue repair. Conversely, caution is warranted for strategies targeting arginase due to potential adverse effects on inflammation resolution and mitochondrial quality control. Future studies should explore the long-term efficacy of arginine-based therapies and their integration with existing antibiotic regimens for optimal TB management. Supplementary Information The online version contains supplementary material available at 10.1186/s44280-025-00070-6.
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Affiliation(s)
- Qingkui Jiang
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ 79103 USA
| | - Ranjeet Kumar
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ 79103 USA
| | - Yi Zhao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523713 China
- Microbiology and Immunology Department, Guangdong Medical University, Dongguan, Guangdong 523808 China
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ 79103 USA
| | - Lanbo Shi
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ 79103 USA
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3
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He X, He Y, Deng X, Lu N, Li A, Gao S, He S, Wang Y, Fu N, Wang Z, Nie Y, Xu L. Rv2741 Promotes Mycobacterium Survival by Modulating Macrophage Function via the IL-1α-MAPK Axis. ACS Infect Dis 2025; 11:676-688. [PMID: 40009799 DOI: 10.1021/acsinfecdis.4c00790] [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: 02/28/2025]
Abstract
One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by Mycobacterium tuberculosis (M. tuberculosis). A distinct family of PE_PGRS proteins, encoded by the M. tuberculosis genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host-pathogen interactions, we created recombinant strains of Mycobacterium smegmatis (M. smegmatis) that expressed the M. tuberculosis Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of M. smegmatis in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of M. tuberculosis.
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Affiliation(s)
- Xintong He
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yonglin He
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xichuan Deng
- Pathogen Biology and Immunology Laboratory, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China
| | - Nan Lu
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Anlong Li
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Sijia Gao
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Shiyan He
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yuran Wang
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Nanzhe Fu
- International Medical School, Chongqing Medical University, Chongqing 400016, China
| | - Zijie Wang
- International Medical School, Chongqing Medical University, Chongqing 400016, China
| | - Yuxin Nie
- The Second Clinical College, Chongqing Medical University, Chongqing 400016, China
| | - Lei Xu
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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4
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Santos AP, Rodrigues LS, Rother N, Mello FCDQ, Magis-Escurra C. The role of neutrophil response in lung damage and post-tuberculosis lung disease: a translational narrative review. Front Immunol 2025; 16:1528074. [PMID: 40124364 PMCID: PMC11925771 DOI: 10.3389/fimmu.2025.1528074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
It is estimated that more than 150 million individuals alive in 2020 had survived tuberculosis (TB). A portion of this large population continues to experience chronic respiratory abnormalities, with or without symptoms, due to previous active pulmonary TB. This condition known as Post-TB Lung Disease (PTLD), involves a complex interaction between pathogen, host and environmental factors. These interactions are believed to drive a hyperinflammatory process in the lungs during active TB, resulting in tissue damage, which may lead to radiological sequelae, impaired pulmonary function, clinical symptoms, such as cough, dyspnea, hemoptysis, and respiratory infections. Such complications impose significant health, financial, and social burdens, which remain poorly understood and inadequately addressed by health care systems. Given the heterogeneity of immune cells and their products infiltrating the airways and the lung parenchyma during acute and chronic inflammation caused by Mycobacterium tuberculosis infection, it is evident that TB immunopathology is multifactorial. Among the various components involved, neutrophils have recently emerged as critical contributors to the deleterious immune response against TB, leading to severe pulmonary damage. In this translational narrative review, we aim to summarize the role of neutrophils and their primary products - proteases (such as elastase), matrix metalloproteinases and neutrophils extracellular traps (NETs) - in pulmonary TB. We highlight new concepts and emerging evidence of neutrophil involvement during the active disease, translating these insights from "bench to bedside" to facilitate dialogue between fundamental researchers and clinical practitioners. Additionally, we present potential targets for future treatment strategies that could mitigate or even prevent PTLD.
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Affiliation(s)
- Ana Paula Santos
- Pulmonary Diseases Department, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil
- Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Department of Respiratory Diseases-TB Expert Center, Radboud University Medical Center, Nijmegen, Netherlands
| | - Luciana Silva Rodrigues
- Department of Pathology and Laboratories, Medical Sciences Faculty, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nils Rother
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | | | - Cecile Magis-Escurra
- Department of Respiratory Diseases-TB Expert Center, Radboud University Medical Center, Nijmegen, Netherlands
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5
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Wynn EA, Dide-Agossou C, Al Mubarak R, Rossmassler K, Ektnitphong V, Bauman AA, Massoudi LM, Voskuil MI, Robertson GT, Moore CM, Walter ND. Emergence of antibiotic-specific Mycobacterium tuberculosis phenotypes during prolonged treatment of mice. Antimicrob Agents Chemother 2025; 69:e0131024. [PMID: 39818957 PMCID: PMC11823617 DOI: 10.1128/aac.01310-24] [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: 09/04/2024] [Accepted: 12/22/2024] [Indexed: 01/19/2025] Open
Abstract
A major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiology of M. tuberculosis (Mtb), which may enable the pathogen to withstand treatment. While antibiotic-treated Mtb has been evaluated in in vitro experiments, it is unclear if and how long-term in vivo treatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affects Mtb physiologic processes differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize the Mtb transcriptome in the BALB/c high-dose aerosol infection mouse model following 4 weeks of treatment with three sterilizing and three non-sterilizing antibiotics. Certain transcriptional changes were shared among most antibiotics, including decreased expression of genes associated with protein synthesis and metabolism and the induction of certain genes associated with stress responses. However, the magnitude of this shared response differed between antibiotics. Sterilizing antibiotics rifampin, pyrazinamide, and bedaquiline generated a more quiescent Mtb state than did non-sterilizing antibiotics isoniazid, ethambutol, and streptomycin, as indicated by the decreased expression of genes associated with translation, transcription, secretion of immunogenic proteins, metabolism, and cell wall synthesis. Additionally, we identified distinguishing transcriptional effects specific to each antibiotic, indicating that different mechanisms of action induce distinct patterns in response to cellular injury. In addition to elucidating the Mtb physiologic changes associated with antibiotic stress, this study demonstrates the value of SEARCH-TB as a highly granular pharmacodynamic assay that reveals antibiotic effects that are not apparent based on culture alone.
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Affiliation(s)
- Elizabeth A. Wynn
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
| | - Christian Dide-Agossou
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Reem Al Mubarak
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Karen Rossmassler
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Victoria Ektnitphong
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
| | - Allison A. Bauman
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
| | - Lisa M. Massoudi
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
| | - Martin I. Voskuil
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Gregory T. Robertson
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
| | - Camille M. Moore
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nicholas D. Walter
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
- Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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6
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Pandey A, Meitei HN, Konjengbam BD, Rahaman H, Haobam R. Association of NOS2A Gene Polymorphisms with Susceptibility to Tuberculosis in Manipuri Population of Northeast India. Biochem Genet 2025:10.1007/s10528-024-11015-w. [PMID: 39776372 DOI: 10.1007/s10528-024-11015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025]
Abstract
Single nucleotide polymorphisms (SNPs) have been reported to influence the activity of specific genes involved with the innate immune response to Mycobacterium; hence, they are crucial in tuberculosis (TB) susceptibility studies. The study aimed to investigate the polymorphism in the NOS2A (Nitric oxide synthase 2A) gene and its association with susceptibility to TB in the Manipuri population of northeast India. This case-control study includes 495 subjects- 220 TB patients and 275 control individuals. TaqMan allelic discrimination assay was used to study the gene polymorphism, and Griess's test was employed to determine the serum nitric oxide (NO) levels. Serum NO levels were analysed to correlate with the functional changes associated with the polymorphisms. Two SNPs of the gene, NOS2A (rs8078340 and rs2274894), were studied. For the SNP-rs8078340, a significant difference in the genotypic and allelic frequencies was observed between the cases and control groups (p = 0.001; AA genotype OR = 30.288, 95% CI: 1.703-538.44 and A allele OR = 2.937, 95% CI: 1.762-4.896). However, for the SNP-rs2274894, only the T allele (with OR = 1.464; 95% CI: 1.080-1.983, p = 0.014) was associated with susceptibility to TB. Serum levels of NO were significantly different between the cases and control groups (p < 0.05). Significant associations of both homozygous AA genotype and allele A of the NOS2A (rs8078340) and minor allele T of NOS2A (rs2274894) were observed with susceptibility to TB. Patients with the AA genotype of NOS2A show a higher NO level, suggesting its role in greater expression of the NOS2A gene.
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Affiliation(s)
- Anupama Pandey
- Department of Biotechnology, Manipur University, Canchipur, Imphal, 795003, Manipur, India
| | | | | | - Hamidur Rahaman
- Department of Biotechnology, Manipur University, Canchipur, Imphal, 795003, Manipur, India
| | - Reena Haobam
- Department of Biotechnology, Manipur University, Canchipur, Imphal, 795003, Manipur, India.
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7
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Yang Q, Zhou Y, Farooq W, Liu Q, Duan J, Xing L, Wu C, Dong L. The immunomodulatory effects of Mesenchymal stem cells on THP-1-derived macrophages against Mycobacterium tuberculosis H37Ra infection. Tuberculosis (Edinb) 2025; 150:102593. [PMID: 39709721 DOI: 10.1016/j.tube.2024.102593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune imbalance is crucial in tuberculosis pathogenesis and may be modulated by mesenchymal stem cells (MSCs). However, how MSCs regulate the host's response to Mycobacterium tuberculosis (Mtb) is unclear. METHODS Human umbilical cord-derived MSCs were co-cultured with Mtb-infected THP-1 macrophages. The intracellular release of ROS in macrophages was measured by DCFH-DA. Cytokine expression was measured by RT-qPCR, apoptosis by Annexin V/PI assay, and pyroptosis markers by Western blotting. Differentially expressed genes (DEGs) in Mtb-infected THP-1 co-cultured with or without MSCs were identified by RNA-seq and potential signaling pathways were analyzed through bioinformatics. RESULTS The fibroblastic morphology of MSCs exhibited 95 % positivity for CD73, CD90, and CD105, while the positivity rate for negative marker HLA-DR was less than 2 %. In Mtb-infected THP-1 macrophages, co-culturing with MSCs increased ROS release, cytokines expression (IL-1β, IL-6, TNF-α), apoptosis, and pyroptosis markers (NLRP3, Caspase-1, and GSDMD). Comparative transcriptome analysis identified 347 up-regulated and 291 down-regulated DEGs, primarily associated with receptor-ligand interactions and enriched in cytokine signaling pathways including JAK-STAT, TNF, ferroptosis, and autophagy. CONCLUSION MSCs could enhance the macrophages' immune response to Mtb by activating immune receptors and inflammatory signaling pathways.
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Affiliation(s)
- Qianwei Yang
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Yiqun Zhou
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Waqas Farooq
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Qimiao Liu
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Jinhui Duan
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Li Xing
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Changxin Wu
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
| | - Li Dong
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
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8
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Jumabayi W, Reyimu A, Zheng R, Paerhati P, Rahman M, Zou X, Xu A. Ferroptosis: A new way to intervene in the game between Mycobacterium tuberculosis and macrophages. Microb Pathog 2024; 197:107014. [PMID: 39396689 DOI: 10.1016/j.micpath.2024.107014] [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] [Received: 08/31/2024] [Revised: 10/06/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
Mycobacterium tuberculosis (Mtb), the main pathogen responsible for the high mortality and morbidity of tuberculosis (TB) worldwide, primarily targets and invades macrophages. Infected macrophages activate a series of immune mechanisms to clear Mtb, however, Mtb evades host immune surveillance through subtle immune escape strategies to create a microenvironment conducive to its own proliferation, growth, and dissemination, while inducing immune cell death. The course of TB is strongly correlated with the form of cell death, including apoptosis, pyroptosis, and necrosis. Recent studies have revealed that ferroptosis, a novel type of programmed cell death characterized by iron-dependent lipid peroxidation, is closely linked to the regulatory mechanisms of TB. The central role of ferroptosis in the pathologic process of TB is increasingly becoming a focal point for exploring new therapeutic targets in this field. This paper will delve into the dynamic game between Mtb and host immune cells, especially the role of ferroptosis in the pathogenesis of TB. At the same time, this paper will analyze the regulatory pathways of ferroptosis and provide unique insights and innovative perspectives for TB therapeutic strategies based on the ferroptosis mechanism. This study not only expands the theoretical basis of TB treatment, but also points out the direction of future drug development, providing new possibilities for overcoming this global health problem.
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Affiliation(s)
- Wuerken Jumabayi
- The Third Clinical Medical College (Affiliated Cancer Hospital) of Xinjiang Medical University, Urumqi, China
| | | | | | | | | | | | - Aimin Xu
- The First People's Hospital of Kashi, Kashi, China.
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9
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Gap-Gaupool B, Glenn SM, Milburn E, Turapov O, Crosatti M, Hincks J, Stewart B, Bacon J, Kendall SL, Voskuil MI, Riabova O, Monakhova N, Green J, Waddell SJ, Makarov VA, Mukamolova GV. Nitric oxide induces the distinct invisibility phenotype of Mycobacterium tuberculosis. Commun Biol 2024; 7:1206. [PMID: 39342050 PMCID: PMC11439070 DOI: 10.1038/s42003-024-06912-0] [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: 11/30/2023] [Accepted: 09/17/2024] [Indexed: 10/01/2024] Open
Abstract
During infection Mycobacterium tuberculosis (Mtb) forms physiologically distinct subpopulations that are recalcitrant to treatment and undetectable using standard diagnostics. These difficult to culture or differentially culturable (DC) Mtb are revealed in liquid media, their revival is often stimulated by resuscitation-promoting factors (Rpf) and prevented by Rpf inhibitors. Here, we investigated the role of nitric oxide (NO) in promoting the DC phenotype. Rpf-dependent DC Mtb were detected following infection of interferon-γ-induced macrophages capable of producing NO, but not when inducible NO synthase was inactivated. After exposure of Mtb to a new donor for sustained NO release (named NOD), the majority of viable cells were Rpf-dependent and undetectable on solid media. Gene expression analyses revealed a broad transcriptional response to NOD, including down-regulation of all five rpf genes. The DC phenotype was partially reverted by over-expression of Rpfs which promoted peptidoglycan remodelling. Thus, NO plays a central role in the generation of Rpf-dependent Mtb, with implications for improving tuberculosis diagnostics and treatments.
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Affiliation(s)
- Brindha Gap-Gaupool
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Sarah M Glenn
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Emily Milburn
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Obolbek Turapov
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Marialuisa Crosatti
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Jennifer Hincks
- FACS Facility Core Biotechnology Services, University of Leicester, Leicester, LE1 9HN, UK
| | - Bradley Stewart
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK
| | - Joanna Bacon
- Discovery Group, Vaccine Development and Evaluation Centre, UK Health Security Agency, Porton Down, SP4 0JG, UK
| | - Sharon L Kendall
- Centre for Endemic, Emerging and Exotic Disease, the Royal Veterinary College, Hatfield, Hertfordshire, AL9 7TA, UK
| | - Martin I Voskuil
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Olga Riabova
- Research Center of Biotechnology, Russian Academy of Sciences, Moscow, Russia
| | - Natalia Monakhova
- Research Center of Biotechnology, Russian Academy of Sciences, Moscow, Russia
| | - Jeffrey Green
- School of Biosciences, University of Sheffield, Sheffield, S10 2TN, UK
| | - Simon J Waddell
- Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, BN1 9PX, UK.
| | - Vadim A Makarov
- Research Center of Biotechnology, Russian Academy of Sciences, Moscow, Russia.
| | - Galina V Mukamolova
- Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, UK.
- The National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester, Leicester, LE1 9HN, UK.
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10
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Wynn EA, Dide-Agossou C, Mubarak RA, Rossmassler K, Ektnitphong V, Bauman AA, Massoudi LM, Voskuil MI, Robertson GT, Moore CM, Walter ND. Emergence of antibiotic-specific Mycobacterium tuberculosis phenotypes during prolonged treatment of mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.20.607990. [PMID: 39229030 PMCID: PMC11370397 DOI: 10.1101/2024.08.20.607990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
A major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiologic state of M. tuberculosis (Mtb) which may enable the pathogen to withstand treatment. While antibiotic-treated Mtb have been evaluated in short-term in vitro experiments, it is unclear if and how long-term in vivo treatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affect Mtb physiologic states differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize the Mtb transcriptome in the BALB/c high-dose aerosol infection mouse model following 4-week treatment with three sterilizing and three non-sterilizing antibiotics. Certain transcriptional changes were concordant among most antibiotics, including decreased expression of genes associated with protein synthesis and metabolism, and the induction of certain genes associated with stress responses. However, the magnitude of this concordant response differed between antibiotics. Sterilizing antibiotics rifampin, pyrazinamide, and bedaquiline generated a more quiescent Mtb state than did non-sterilizing antibiotics isoniazid, ethambutol, and streptomycin, as indicated by decreased expression of genes associated with translation, transcription, secretion of immunogenic proteins, metabolism, and cell wall synthesis. Additionally, we identified distinguishing transcriptional effects specific to each antibiotic, indicating that different mechanisms of action induce distinct patterns of cellular injury. In addition to elucidating Mtb physiologic changes associated with antibiotic stress, this study demonstrates the value of SEARCH-TB as a highly granular pharmacodynamic assay that reveals antibiotic effects that are not apparent based on culture alone.
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Affiliation(s)
- Elizabeth A Wynn
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
| | - Christian Dide-Agossou
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Reem Al Mubarak
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Karen Rossmassler
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Linda Crnic Institute for Down syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Victoria Ektnitphong
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Allison A Bauman
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Lisa M Massoudi
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Martin I Voskuil
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Gregory T Robertson
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Camille M Moore
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nicholas D Walter
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
- Consortium for Applied Microbial Metrics, Aurora, CO, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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11
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Tanweer S, Sharma T, Grover A, Agarwal M, Grover S. Mycobacterium tuberculosis Essential Gene Thymidylate Synthase Is Involved in Immune Modulation and Survival inside the Host. ACS OMEGA 2024; 9:33743-33750. [PMID: 39130601 PMCID: PMC11308015 DOI: 10.1021/acsomega.4c02919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 08/13/2024]
Abstract
A Mycobacterium tuberculosis essential gene, ThyX (Rv2754c), plays a key role in intermediate metabolism and respiration by catalyzing the formation of dTMP and tetrahydrofolate from dUMP and methylenetetrahydrofolate. ThyX is present in the M.tb complex and in M. smegmatis a nonpathogenic strain of Mycobacteria. In this study, we identified a novel function of ThyX, an enzyme with immune-modulating properties. We have shown that ThyX can activate the macrophages in the host toward M1 response. Overexpression of ThyX stimulates the production of nitrite oxide (NO) and induces apoptosis in macrophages; indeed both responses help the host to control growth of M.tb. ThyX was also discovered to play a role in the recombinant bacterium's ability to survive when it was subjected to oxidative and hypoxic stress by macrophages. These findings demonstrate the protein's functional importance in M.tb. Indeed these findings represent ThyX as a potential candidate for future research and show this as a therapeutic target.
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Affiliation(s)
- Sana Tanweer
- Department
of Molecular Medicine, Jamia Hamdard, New Delhi-110065, India
| | - Tarina Sharma
- New
Jersey Medical School, Rutgers, The State
University of New Jersey, Newark, New Jersey 07103, United States
| | - Abhinav Grover
- School
of Biotechnology, Jawaharlal University, New Delhi-110069, India
| | - Meetu Agarwal
- Department
of Molecular Medicine, Jamia Hamdard, New Delhi-110065, India
| | - Sonam Grover
- Department
of Molecular Medicine, Jamia Hamdard, New Delhi-110065, India
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12
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Lai R, Williams T, Rakib T, Lee J, Behar SM. Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is modulated by T cells. Nat Commun 2024; 15:5710. [PMID: 38977711 PMCID: PMC11231272 DOI: 10.1038/s41467-024-48515-7] [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: 10/16/2023] [Accepted: 05/03/2024] [Indexed: 07/10/2024] Open
Abstract
Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.
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Affiliation(s)
- Rocky Lai
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Travis Williams
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Tasfia Rakib
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jinhee Lee
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Samuel M Behar
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
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13
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Guallar-Garrido S, Soldati T. Exploring host-pathogen interactions in the Dictyostelium discoideum-Mycobacterium marinum infection model of tuberculosis. Dis Model Mech 2024; 17:dmm050698. [PMID: 39037280 PMCID: PMC11552500 DOI: 10.1242/dmm.050698] [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] [Indexed: 07/23/2024] Open
Abstract
Mycobacterium tuberculosis is a pathogenic mycobacterium that causes tuberculosis. Tuberculosis is a significant global health concern that poses numerous clinical challenges, particularly in terms of finding effective treatments for patients. Throughout evolution, host immune cells have developed cell-autonomous defence strategies to restrain and eliminate mycobacteria. Concurrently, mycobacteria have evolved an array of virulence factors to counteract these host defences, resulting in a dynamic interaction between host and pathogen. Here, we review recent findings, including those arising from the use of the amoeba Dictyostelium discoideum as a model to investigate key mycobacterial infection pathways. D. discoideum serves as a scalable and genetically tractable model for human phagocytes, providing valuable insights into the intricate mechanisms of host-pathogen interactions. We also highlight certain similarities between M. tuberculosis and Mycobacterium marinum, and the use of M. marinum to more safely investigate mycobacteria in D. discoideum.
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Affiliation(s)
- Sandra Guallar-Garrido
- Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
| | - Thierry Soldati
- Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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14
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Sharma J, Mudalagiriyappa S, Abdelaal HFM, Kelly TC, Choi W, Ponnuraj N, Vieson MD, Talaat AM, Nanjappa SG. E3 ubiquitin ligase CBLB regulates innate immune responses and bacterial dissemination during nontuberculous mycobacteria infection. J Leukoc Biol 2024; 115:1118-1130. [PMID: 38271280 PMCID: PMC11135617 DOI: 10.1093/jleuko/qiae019] [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: 08/04/2023] [Revised: 11/27/2023] [Accepted: 12/20/2023] [Indexed: 01/27/2024] Open
Abstract
Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens causing pulmonary infection to fatal disseminated disease. NTM infections are steadily increasing in children and adults, and immune-compromised individuals are at a greater risk of fatal infections. The NTM disease's adverse pathology and resistance to antibiotics have further worsened the therapeutic measures. Innate immune regulators are potential targets for therapeutics to NTM, especially in a T cell-suppressed population, and many ubiquitin ligases modulate pathogenesis and innate immunity during infections, including mycobacterial infections. Here, we investigated the role of an E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (CBLB), in immunocompromised mouse models of NTM infection. We found that CBLB is essential to prevent bacterial growth and dissemination. Cblb deficiency debilitated natural killer cells, inflammatory monocytes, and macrophages in vivo. However, Cblb deficiency in macrophages did not wane its ability to inhibit bacterial growth or production of reactive oxygen species or interferon γ production by natural killer cells in vitro. CBLB restricted NTM growth and dissemination by promoting early granuloma formation in vivo. Our study shows that CBLB bolsters innate immune responses and helps prevent the dissemination of NTM during compromised T cell immunity.
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Affiliation(s)
- Jaishree Sharma
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
| | - Srinivasu Mudalagiriyappa
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
| | - Hazem F M Abdelaal
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, Madison, WI 53706, United States
| | - Thomas C Kelly
- Integrative Biology Honors Program, University Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Woosuk Choi
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
| | - Nagendraprabhu Ponnuraj
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
| | - Miranda D Vieson
- Veterinary Diagnostic Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
| | - Adel M Talaat
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, Madison, WI 53706, United States
| | - Som Gowda Nanjappa
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States
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15
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Granados-Tristán AL, Hernández-Luna CE, González-Escalante LA, Camacho-Moll ME, Silva-Ramírez B, Bermúdez de León M, Peñuelas-Urquides K. ESX-3 secretion system in Mycobacterium: An overview. Biochimie 2024; 216:46-55. [PMID: 37879428 DOI: 10.1016/j.biochi.2023.10.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/26/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
Mycobacteria are microorganisms distributed in the environment worldwide, and some of them, such as Mycobacterium tuberculosis or M. leprae, are pathogenic. The hydrophobic mycobacterial cell envelope has low permeation and bacteria need to export products across their structure. Mycobacteria possess specialized protein secretion systems, such as the Early Secretory Antigenic Target 6 secretion (ESX) system. Five ESX loci have been described in M. tuberculosis, called ESX-1 to ESX-5. The ESX-3 secretion system has been associated with mycobacterial metabolism and growth. The locus of this system is highly conserved across mycobacterial species. Metallo-proteins regulate negative ESX-3 transcription in high conditions of iron and zinc. Moreover, this secretion system is part of an antioxidant regulatory pathway linked to Zinc. EccA3, EccB3, EccC3, EccD3, and EccE3 are components of the ESX-3 secretion machinery, whereas EsxG-EsxH, PE5-PPE4, and PE15-PPE20 are proteins secreted by this system. In addition, EspG3 and MycP3 are complementary proteins involved in transport and proteolysis respectively. This system is associated to mycobacterial virulence by releasing the bacteria from the phagosome and inhibiting endomembrane damage response. Furthermore, components of this system inhibit the host immune response by reducing the recognition of M. tuberculosis-infected cells. The components of the ESX-3 secretion system play a role in drug resistance and cell wall integrity. Moreover, the expression data of this system indicated that external and internal factors affect ESX-3 locus expression. This review provides an overview of new findings on the ESX-3 secretion system, its regulation, expression, and functions.
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Affiliation(s)
- Ana Laura Granados-Tristán
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico; Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, San Nicolás de los Garza, 66455, Nuevo León, Mexico.
| | - Carlos Eduardo Hernández-Luna
- Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, San Nicolás de los Garza, 66455, Nuevo León, Mexico.
| | - Laura Adiene González-Escalante
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico.
| | - María Elena Camacho-Moll
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico.
| | - Beatriz Silva-Ramírez
- Departamento de Inmunogenética, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico.
| | - Mario Bermúdez de León
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico.
| | - Katia Peñuelas-Urquides
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, 64720, Nuevo León, Mexico.
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16
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Zhuang L, Yang L, Li L, Ye Z, Gong W. Mycobacterium tuberculosis: immune response, biomarkers, and therapeutic intervention. MedComm (Beijing) 2024; 5:e419. [PMID: 38188605 PMCID: PMC10771061 DOI: 10.1002/mco2.419] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 01/09/2024] Open
Abstract
Although tuberculosis (TB) is an infectious disease, the progression of the disease following Mycobacterium tuberculosis (MTB) infection is closely associated with the host's immune response. In this review, a comprehensive analysis of TB prevention, diagnosis, and treatment was conducted from an immunological perspective. First, we delved into the host's immune response mechanisms against MTB infection as well as the immune evasion mechanisms of the bacteria. Addressing the challenges currently faced in TB diagnosis and treatment, we also emphasized the importance of protein, genetic, and immunological biomarkers, aiming to provide new insights for early and personalized diagnosis and treatment of TB. Building upon this foundation, we further discussed intervention strategies involving chemical and immunological treatments for the increasingly critical issue of drug-resistant TB and other forms of TB. Finally, we summarized TB prevention, diagnosis, and treatment challenges and put forward future perspectives. Overall, these findings provide valuable insights into the immunological aspects of TB and offer new directions toward achieving the WHO's goal of eradicating TB by 2035.
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Affiliation(s)
- Li Zhuang
- Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and TreatmentSenior Department of Tuberculosis, the Eighth Medical Center of PLA General HospitalBeijingChina
- Senior Department of TuberculosisHebei North UniversityZhangjiakouHebeiChina
| | - Ling Yang
- Senior Department of TuberculosisHebei North UniversityZhangjiakouHebeiChina
| | - Linsheng Li
- Senior Department of TuberculosisHebei North UniversityZhangjiakouHebeiChina
| | - Zhaoyang Ye
- Senior Department of TuberculosisHebei North UniversityZhangjiakouHebeiChina
| | - Wenping Gong
- Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and TreatmentSenior Department of Tuberculosis, the Eighth Medical Center of PLA General HospitalBeijingChina
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17
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Lai R, Williams T, Rakib T, Lee J, Behar SM. Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.29.569283. [PMID: 38076803 PMCID: PMC10705395 DOI: 10.1101/2023.11.29.569283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.
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Affiliation(s)
- Rocky Lai
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Travis Williams
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Tasfia Rakib
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Jinhee Lee
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Samuel M. Behar
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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18
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Abdalla AE, Alanazi A, Abosalif KOA, Alameen AAM, Junaid K, Manni E, Talha AA, Ejaz H. MicroRNA-155, a double-blade sword regulator of innate tuberculosis immunity. Microb Pathog 2023; 185:106438. [PMID: 37925110 DOI: 10.1016/j.micpath.2023.106438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/06/2023]
Abstract
Tuberculosis (TB) is a chronic, life-threatening disease caused by unusual facultative intracellular bacteria, Mycobacterium tuberculosis. This bacterium has unique resistance to many antimicrobial agents and has become a major global health concern due to emerging multidrug-resistant strains. Additionally, it has developed multiple schemes to exploit host immune signaling and establish long-term survival within host tissues. Thus, understanding the pathways that govern the crosstalk between the bacterium and the immune system could provide a new avenue for therapeutic interventions. MicroRNAs (miRs) are short, noncoding, and regulator RNA molecules that control the expression of cellular genes by targeting their mRNAs post-transcriptionally. MiR-155 is one of the most crucial miR in shaping the host immune defenses against M. tuberculosis. MiR-155 is remarkably downregulated in patients with clear clinical TB symptoms in comparison with latently infected patients and/or healthy individuals, thereby implicating its role in controlling M. tuberculosis infection. However, functional probing of miR-155 suggests dual effects in regulating the host's innate defenses in response to mycobacterial infection. This review provides comprehensive knowledge and future perspectives regarding complex signaling pathways that mediated miR-155 expression during M. tuberculosis infections. Moreover, miR-155-targeting signaling orchestrates inflammatory mediators' production, apoptosis, and autophagy.
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Affiliation(s)
- Abualgasim Elgaili Abdalla
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia.
| | - Awadh Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Khalid Omer Abdalla Abosalif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Ayman Ali Mohammed Alameen
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Kashaf Junaid
- School of Biological and Behavioural Sciences, Queen Mary University of London, London, E1 4NS, UK
| | - Emad Manni
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Albadawi Abdelbagi Talha
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Hasan Ejaz
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia.
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19
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Khan SA, Shakoor A. Recent Strategies and Future Recommendations for the Fabrication of Antimicrobial, Antibiofilm, and Antibiofouling Biomaterials. Int J Nanomedicine 2023; 18:3377-3405. [PMID: 37366489 PMCID: PMC10290865 DOI: 10.2147/ijn.s406078] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/06/2023] [Indexed: 06/28/2023] Open
Abstract
Biomaterials and biomedical devices induced life-threatening bacterial infections and other biological adverse effects such as thrombosis and fibrosis have posed a significant threat to global healthcare. Bacterial infections and adverse biological effects are often caused by the formation of microbial biofilms and the adherence of various biomacromolecules, such as platelets, proteins, fibroblasts, and immune cells, to the surfaces of biomaterials and biomedical devices. Due to the programmed interconnected networking of bacteria in microbial biofilms, they are challenging to treat and can withstand several doses of antibiotics. Additionally, antibiotics can kill bacteria but do not prevent the adsorption of biomacromolecules from physiological fluids or implanting sites, which generates a conditioning layer that promotes bacteria's reattachment, development, and eventual biofilm formation. In these viewpoints, we highlighted the magnitude of biomaterials and biomedical device-induced infections, the role of biofilm formation, and biomacromolecule adhesion in human pathogenesis. We then discussed the solutions practiced in healthcare systems for curing biomaterials and biomedical device-induced infections and their limitations. Moreover, this review comprehensively elaborated on the recent advances in designing and fabricating biomaterials and biomedical devices with these three properties: antibacterial (bacterial killing), antibiofilm (biofilm inhibition/prevention), and antibiofouling (biofouling inhibition/prevention) against microbial species and against the adhesion of other biomacromolecules. Besides we also recommended potential directions for further investigations.
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Affiliation(s)
- Shakeel Ahmad Khan
- Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hung Hom, Kowloon, 999077, Hong Kong
| | - Adnan Shakoor
- Department of Control and Instrumentation Engineering, King Fahd University of Petroleum & Minerals, Dhahran, Saudi Arabia
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20
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Marques HM. The inorganic chemistry of the cobalt corrinoids - an update. J Inorg Biochem 2023; 242:112154. [PMID: 36871417 DOI: 10.1016/j.jinorgbio.2023.112154] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 02/05/2023]
Abstract
The inorganic chemistry of the cobalt corrinoids, derivatives of vitamin B12, is reviewed, with particular emphasis on equilibrium constants for, and kinetics of, their axial ligand substitution reactions. The role the corrin ligand plays in controlling and modifying the properties of the metal ion is emphasised. Other aspects of the chemistry of these compounds, including their structure, corrinoid complexes with metals other than cobalt, the redox chemistry of the cobalt corrinoids and their chemical redox reactions, and their photochemistry are discussed. Their role as catalysts in non-biological reactions and aspects of their organometallic chemistry are briefly mentioned. Particular mention is made of the role that computational methods - and especially DFT calculations - have played in developing our understanding of the inorganic chemistry of these compounds. A brief overview of the biological chemistry of the B12-dependent enzymes is also given for the reader's convenience.
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Affiliation(s)
- Helder M Marques
- Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg 2050, South Africa.
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21
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Lanni F, Wijnant GJ, Xie M, Osiecki P, Dartois V, Sarathy JP. Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis. Tuberculosis (Edinb) 2023; 139:102318. [PMID: 36889104 DOI: 10.1016/j.tube.2023.102318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/28/2022] [Accepted: 01/22/2023] [Indexed: 01/24/2023]
Abstract
As a facultative intracellular pathogen, M. tuberculosis (Mtb) is highly adapted to evading antibacterial mechanisms in phagocytic cells. Both the macrophage and pathogen experience transcriptional and metabolic changes from the onset of phagocytosis. To account for this interaction in the assessment of intracellular drug susceptibility, we allowed a 3-day preadaptation phase post-macrophage infection prior to drug treatment. We found that intracellular Mtb in human monocyte-derived macrophages (MDM) presents dramatic alterations in susceptibility to isoniazid, sutezolid, rifampicin and rifapentine when compared to axenic culture. Infected MDM gradually accumulate lipid bodies, adopting a characteristic appearance reminiscent of foamy macrophages in granulomas. Furthermore, TB granulomas in vivo develop hypoxic cores with decreasing oxygen tension gradients across their radii. Accordingly, we evaluated the effects of hypoxia on preadapted intracellular Mtb in our MDM model. We observed that hypoxia induced greater lipid body formation and no additional shifts in drug tolerance, suggesting that the adaptation of intracellular Mtb to baseline host cell conditions under normoxia dominates changes to intracellular drug susceptibility. Using unbound plasma concentrations in patients as surrogates for free drug concentrations in lung interstitial fluid, we estimate that intramacrophage Mtb in granulomas are exposed to bacteriostatic concentrations of most study drugs.
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Affiliation(s)
- Faye Lanni
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States
| | - Gert-Jan Wijnant
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States
| | - Min Xie
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States
| | - Paulina Osiecki
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States
| | - Véronique Dartois
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States; Hackensack School of Medicine, Department of Medical Sciences, 123, Metro Boulevard, Nutley, NJ, 07110, United States
| | - Jansy P Sarathy
- Center for Discovery and Innovation, 111 Ideation Way, Nutley, NJ, 07110, United States.
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22
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Sánchez-Barinas CD, Vergara-Vanegas V, Gamboa-Hernández CM, Ocampo M, Cuello-Oliveros A, Patarroyo MA, Patarroyo ME. Peptide-pulsed dendritic cells' immunomodulating effect regarding Mycobacterium tuberculosis growth in macrophages. Immunobiology 2023; 228:152346. [PMID: 36805110 DOI: 10.1016/j.imbio.2023.152346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023]
Abstract
Mycobacterium tuberculosis is one of the most successful pathogens affecting humans, being the main cause of tuberculosis. It accounts for most infectious agent-related deaths worldwide; it has been estimated that a third of the world's population are bacillus carriers. This pathogen's evolutionary adaptation is mainly due to its ability to block a host's immune system by preventing it using an effective immune response in cases of active tuberculosis. Peptide-based synthetic vaccines represent an alternative for counteracting tuberculosis; however, although peptide antigens can be identified, they are not recognised by a host's immune system. An approach using dendritic cells as immunomodulating agents for increasing synthetic peptides' antigenic capacity has thus been advanced. Dendritic cells obtained from IL to 4- and GM-CSF-treated peripheral blood mononuclear cells were pulsed with synthetic Mtb protein peptides which have been reported as participating in mycobacteria-host interactions; their amino acid sequences were modified to improve MHC-II coupling and thus increase their recognition by a host's immune system. pMHC-II/TCR interaction triggered a lymphocyte response which controlled Mtb intracellular growth in infected macrophages. This work has been aimed at contributing to understanding dendritic cells' role in Mycobacterium tuberculosis protein peptide antigen presentation, thereby increasing individuals' immune response as a means of controlling the disease.
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Affiliation(s)
- Christian D Sánchez-Barinas
- Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 No. 26-20, postcode: 111321, Bogotá, Colombia; Universidad Nacional de Colombia, Carrera 45 No. 26-85, postcode: 111321, Bogotá, Colombia
| | | | | | - Marisol Ocampo
- Universidad Distrital Francisco José de Caldas, Carrera 3 # 26A - 40, postcode: 110311, Bogotá, Colombia.
| | - Angela Cuello-Oliveros
- Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 No. 26-20, postcode: 111321, Bogotá, Colombia
| | - Manuel A Patarroyo
- Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 No. 26-20, postcode: 111321, Bogotá, Colombia; Universidad Nacional de Colombia, Carrera 45 No. 26-85, postcode: 111321, Bogotá, Colombia
| | - Manuel E Patarroyo
- Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 No. 26-20, postcode: 111321, Bogotá, Colombia; Universidad Nacional de Colombia, Carrera 45 No. 26-85, postcode: 111321, Bogotá, Colombia
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Shi X, Li C, Cheng L, Ullah H, Sha S, Kang J, Ma X, Ma Y. Mycobacterium tuberculosis Rv1324 Protein Contributes to Mycobacterial Persistence and Causes Pathological Lung Injury in Mice by Inducing Ferroptosis. Microbiol Spectr 2023; 11:e0252622. [PMID: 36625672 PMCID: PMC9927160 DOI: 10.1128/spectrum.02526-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Mycobacterium tuberculosis (Mtb) is the pathogenic agent of tuberculosis (TB). Intracellular survival plays a central role in the pathogenesis of Mtb, a process that depends on an array of virulence factors for Mtb to colonize and proliferate within a host. Reactive nitrogen and oxygen species (RNS and ROS) are among the most effective antimycobacterial molecules generated by the host during infection. However, Mtb has evolved a number of proteins and enzymes to detoxify ROS and RNS. Secretory protein Rv1324, as a possible thioredoxin, might also have oxidoreductase activity against ROS and RNS during Mtb infection, and it is a potential virulence factor of Mtb. In this study, we investigated the biochemical properties of Mtb Rv1324 and its role in mycobacterial survival and virulence. The results showed that the Rv1324 protein had antioxidant activity and increased the survival of M. smegmatis that was exposed to ROS and RNS. In addition, Rv1324 enhanced the colonization ability of M. smegmatis in the lungs of mice. Further, mice infected with M. smegmatis harboring Rv1324 exhibited pathological injury and inflammation in the lung, which was mediated by ferroptosis. In summary, this study advances our understanding of the mechanisms of mycobacterial survival and pathogenesis, and it reveals a novel target for TB treatment. IMPORTANCE The intracellular survival of M. tuberculosis (Mtb) plays a crucial role in its pathogenesis, which depends on various Mtb oxidoreductases that are resistant to reactive oxygen and nitrogen species (ROS and RNS) that are generated by the host during Mtb infection. Secretory protein Rv1324 is a potential virulence factor of Mtb and is a possible thioredoxin that has oxidoreductase activity against ROS and RNS during Mtb infection. We investigated the biochemical properties of Mtb Rv1324 and its role in mycobacterial survival and virulence. It was confirmed that the Rv1324 protein had antioxidant activity and an increased mycobacterial resistance to ROS and RNS. In addition, Rv1324 enhanced mycobacterial persistence and induced pathological injury and inflammation in the lungs of mice by activating ferroptosis. This study advances our understanding of the mechanisms of mycobacterial survival and pathogenesis, and it reveals a novel target for TB treatment.
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Affiliation(s)
- Xiaoxia Shi
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
- Department of Experimental Teaching Center of Public Health, Dalian Medical University, Dalian, China
| | - Chunyu Li
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Lin Cheng
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Hayan Ullah
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Shanshan Sha
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Jian Kang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Xiaochi Ma
- College of Integrative Medicine, Dalian Medical University, Dalian, China
- Pharmaceutical Research Center, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yufang Ma
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
- Department of Microbiology, Dalian Medical University, Dalian, China
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24
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Lin W, Fan S, Liao K, Huang Y, Cong Y, Zhang J, Jin H, Zhao Y, Ruan Y, Lu H, Yang F, Wu C, Zhao D, Fu Z, Zheng B, Xu JF, Pi J. Engineering zinc oxide hybrid selenium nanoparticles for synergetic anti-tuberculosis treatment by combining Mycobacterium tuberculosis killings and host cell immunological inhibition. Front Cell Infect Microbiol 2023; 12:1074533. [PMID: 36776549 PMCID: PMC9908760 DOI: 10.3389/fcimb.2022.1074533] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/28/2022] [Indexed: 01/27/2023] Open
Abstract
Introduction As a deadly disease induced by Mycobacterium tuberculosis (Mtb), tuberculosis remains one of the top killers among infectious diseases. The low intracellular Mtb killing efficiency of current antibiotics introduced the long duration anti-TB therapy in clinic with strong side effects and increased drug-resistant mutants. Therefore, the exploration of novel anti-TB agents with potent anti-TB efficiency becomes one of the most urgent issues for TB therapies. Methods Here, we firstly introduced a novel method for the preparation of zinc oxide-selenium nanoparticles (ZnO-Se NPs) by the hybridization of zinc oxide and selenium to combine the anti-TB activities of zinc oxide nanoparticles and selenium nanoparticles. We characterized the ZnO-Se NPs by dynamic laser light scattering and transmission electron microscopy, and then tested the inhibition effects of ZnO-Se NPs on extracellular Mtb by colony-forming units (CFU) counting, bacterial ATP analysis, bacterial membrane potential analysis and scanning electron microscopy imaging. We also analyzed the effects of ZnO-Se NPs on the ROS production, mitochondrial membrane potential, apoptosis, autophagy, polarization and PI3K/Akt/mTOR signaling pathway of Mtb infected THP-1 macrophages. At last, we also tested the effects of ZnO-Se NPs on intracellular Mtb in THP-1 cells by colony-forming units (CFU) counting. Results The obtained spherical core-shell ZnO-Se NPs with average diameters of 90 nm showed strong killing effects against extracellular Mtb, including BCG and the virulent H37Rv, by disrupting the ATP production, increasing the intracellular ROS level and destroying the membrane structures. More importantly, ZnO-Se NPs could also inhibit intracellular Mtb growth by promoting M1 polarization to increase the production of antiseptic nitric oxide and also promote apoptosis and autophagy of Mtb infected macrophages by increasing the intracellular ROS, disrupting mitochondria membrane potential and inhibiting PI3K/Akt/mTOR signaling pathway. Discussion These ZnO-Se NPs with synergetic anti-TB efficiency by combining the Mtb killing effects and host cell immunological inhibition effects were expected to serve as novel anti-TB agents for the development of more effective anti-TB strategy.
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Affiliation(s)
- Wensen Lin
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Shuhao Fan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Kangsheng Liao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yifan Huang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanguang Cong
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Junai Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Hua Jin
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Yi Zhao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Hongmei Lu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Fen Yang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Changxian Wu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Daina Zhao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Zhendong Fu
- Songshan Lake Materials Laboratory, Dongguan, China
| | - Biying Zheng
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China,*Correspondence: Biying Zheng, ; Jun-Fa Xu, ; Jiang Pi,
| | - Jun-Fa Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China,*Correspondence: Biying Zheng, ; Jun-Fa Xu, ; Jiang Pi,
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China,*Correspondence: Biying Zheng, ; Jun-Fa Xu, ; Jiang Pi,
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Cioetto-Mazzabò L, Boldrin F, Beauvineau C, Speth M, Marina A, Namouchi A, Segafreddo G, Cimino M, Favre-Rochex S, Balasingham S, Trastoy B, Munier-Lehmann H, Griffiths G, Gicquel B, Guerin M, Manganelli R, Alonso-Rodríguez N. SigH stress response mediates killing of Mycobacterium tuberculosis by activating nitronaphthofuran prodrugs via induction of Mrx2 expression. Nucleic Acids Res 2022; 51:144-165. [PMID: 36546765 PMCID: PMC9841431 DOI: 10.1093/nar/gkac1173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/17/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
The emergence of drug-resistant Mycobacterium tuberculosis strains highlights the need to discover anti-tuberculosis drugs with novel mechanisms of action. Here we discovered a mycobactericidal strategy based on the prodrug activation of selected chemical derivatives classified as nitronaphthofurans (nNFs) mediated by the coordinated action of the sigH and mrx2 genes. The transcription factor SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in M. tuberculosis. The nNF action induced the SigH stress response which in turn induced the mrx2 overexpression. The nitroreductase Mrx2 was found to activate nNF prodrugs, killing replicating, non-replicating and intracellular forms of M. tuberculosis. Analysis of SigH DNA sequences obtained from spontaneous nNF-resistant M. tuberculosis mutants suggests disruption of SigH binding to the mrx2 promoter site and/or RNA polymerase core, likely promoting the observed loss of transcriptional control over Mrx2. Mutations found in mrx2 lead to structural defects in the thioredoxin fold of the Mrx2 protein, significantly impairing the activity of the Mrx2 enzyme against nNFs. Altogether, our work brings out the SigH/Mrx2 stress response pathway as a promising target for future drug discovery programs.
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Affiliation(s)
| | | | - Claire Beauvineau
- Chemical Library Institut Curie/CNRS, CNRS UMR9187, INSERM U1196 and CNRS UMR3666, INSERM U1193, Université Paris-Saclay, Orsay 91405, France
| | - Martin Speth
- Department Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo 0371, Norway
| | - Alberto Marina
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio 48160 Spain
| | - Amine Namouchi
- Génétique Mycobactérienne, Institute Pasteur, Paris 75015, France,Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Oslo 0371, Norway
| | - Greta Segafreddo
- Department of Molecular Medicine, University of Padova, Padova 35122, Italy
| | - Mena Cimino
- Génétique Mycobactérienne, Institute Pasteur, Paris 75015, France
| | | | | | - Beatriz Trastoy
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio 48160 Spain,Structural Glycobiology Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Bizkaia 48903, Spain
| | - Hélène Munier-Lehmann
- Département de Biologie Structurale et Chimie, Institut Pasteur, CNRS UMR3523, Université de Paris, Paris 75015, France
| | - Gareth Griffiths
- Department Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo 0371, Norway
| | - Brigitte Gicquel
- Génétique Mycobactérienne, Institute Pasteur, Paris 75015, France,Department of Tuberculosis Control and Prevention, Shenzhen Nanshan Centre for Chronic Disease Control, Shenzhen 518054, China
| | - Marcelo E Guerin
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio 48160 Spain,Structural Glycobiology Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Bizkaia 48903, Spain,IKERBASQUE, Basque Foundation for Science, Bilbao 48009, Spain
| | - Riccardo Manganelli
- Correspondence may also be addressed to Riccardo Manganelli. Tel: +39 049 827 2366; Fax: +39 049 827 2355;
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26
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Zhou X, Zhang Z, Xu H, Zhu B, Zhang L, Lie L, Huang Y, Du X, Liu H, Li Y, Huang Y, Hu S, Zhou C, Wen Q, Pepplenbosch MP, Ma L. Viperin impairs the innate immune response through the IRAK1-TRAF6-TAK1 axis to promote Mtb infection. Sci Signal 2022; 15:eabe1621. [PMID: 36194648 DOI: 10.1126/scisignal.abe1621] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Mycobacterium tuberculosis (Mtb) infection is a long-standing public health threat, and the development of host-directed therapy for eradicating Mtb infection requires better insights into Mtb-host interactions. Viperin [virus-inhibitory protein, endoplasmic reticulum-associated, interferon (IFN) inducible] is an IFN-inducible protein with broad antiviral activities. Here, we demonstrated that Viperin was increased in abundance in patients with lymphatic and pulmonary tuberculosis (TB). Viperin-deficient mice had decreased Mtb bacterial loads and enhanced macrophage responses compared with their wild-type counterparts. Viperin suppressed the formation of a complex containing interleukin-1 receptor-associated kinase 1, TNF receptor-associated factor 6, and transforming growth factor β-activated kinase 1 (TAK1) and inhibited the TAK1-dependent activation of IκB kinase α/β, thereby impairing the production of nitric oxide and proinflammatory cytokines. These results suggest that Viperin promotes Mtb infection by inhibiting host innate immune responses in macrophages, suggesting that Viperin may be a candidate target for adjunct host-directed therapy in patients with TB.
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Affiliation(s)
- Xinying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Zelin Zhang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Hui Xu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Bo Zhu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Lijie Zhang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Linmiao Lie
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yingqi Huang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xialin Du
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Honglin Liu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yanfen Li
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yulan Huang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Shengfeng Hu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Chaoying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Qian Wen
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Mailkel P Pepplenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Li Ma
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
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Parbhoo T, Mouton JM, Sampson SL. Phenotypic adaptation of Mycobacterium tuberculosis to host-associated stressors that induce persister formation. Front Cell Infect Microbiol 2022; 12:956607. [PMID: 36237425 PMCID: PMC9551238 DOI: 10.3389/fcimb.2022.956607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
Mycobacterium tuberculosis exhibits a remarkable ability to interfere with the host antimicrobial response. The pathogen exploits elaborate strategies to cope with diverse host-induced stressors by modulating its metabolism and physiological state to prolong survival and promote persistence in host tissues. Elucidating the adaptive strategies that M. tuberculosis employs during infection to enhance persistence is crucial to understanding how varying physiological states may differentially drive disease progression for effective management of these populations. To improve our understanding of the phenotypic adaptation of M. tuberculosis, we review the adaptive strategies employed by M. tuberculosis to sense and coordinate a physiological response following exposure to various host-associated stressors. We further highlight the use of animal models that can be exploited to replicate and investigate different aspects of the human response to infection, to elucidate the impact of the host environment and bacterial adaptive strategies contributing to the recalcitrance of infection.
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Tenriola A, Hidayah N, Subair, Massi MN, Halik H, Damayanti T, Jafriati, Rivai ATO. Analysis of real-time PCR Melanocortin 3 ( MC3R) gene expression to identify new biomarkers inflammation in tuberculosis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022; 23:111. [PMID: 37521838 PMCID: PMC9294815 DOI: 10.1186/s43042-022-00323-8] [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: 04/11/2022] [Accepted: 07/12/2022] [Indexed: 11/10/2022] Open
Abstract
Background Diagnosis of tuberculosis (TB) in the era of technological sophistication requires accuracy and speed to provide as much information as possible so that TB treatment can be carried out quickly and precisely. New studies have also begun to be carried out to diagnose TB, one of which is by examining genes, either by looking at polymorphisms, mutations, or expressions. Several previous studies have confirmed the association of MC3R and TB genes with polymorphisms; MC3R is a gene that participates in the regulation of the inflammatory process and is also found in macrophages; therefore, we tried to analyze gene expression in the active TB group, household contacts, and healthy controls for looked at the differences between the three groups and confirmed the correlation of MC3R with TB by seeing which group's gene expression increased the most expression of the three groups so that the results can be considered as a TB diagnostic biomarker in the future. Methods This study included 122 people, 49 patients with confirmed TB, 46 close relatives of patients, and 27 healthy controls. This study used a real-time PCR technique to analyze MC3R gene expression in the three groups, and all data were analyzed using Bio-Rad CFXTM software version 3.1 and one-way ANOVA using SPSS 21.0. Results The value of MC3R gene expression in the active TB group increased 3.6-fold in the healthy group (p = 0.143), and that of gene expression in the healthy control group increased 1.09-fold in the healthy group (p = 0.007). Conclusion There is a relationship between MC3R and TB based on the results of gene expression analysis that increased in the active TB group compared to the household contact group and healthy controls.
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Affiliation(s)
- Andi Tenriola
- Postgraduate Program, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Najdah Hidayah
- Postgraduate Program, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Subair
- Postgraduate Program, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Muhammad Nasrum Massi
- Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Handayani Halik
- Postgraduate Program, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Tri Damayanti
- Postgraduate Program, Faculty of Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan Km.10, Makassar, Sulawesi Selatan 90245 Indonesia
| | - Jafriati
- Department of Public Health Study Program, Faculty of Public Health, Universitas Halu Oleo, Kampus Hijau Bumi Tridharma, Anduonohu, Kec. Kambu, Kota Kendari, Sulawesi Tenggara 93232 Indonesia
| | - Andi Tenri Ola Rivai
- Universitas Islam Negeri Alauddin, Makassar, Jl. Sultan Alauddin No. 63, Romangpolong, Kec. Somba Opu, Kabupaten Gowa, Sulawesi Selatan 92113 Indonesia
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Magnoliae flos Downregulated Lipopolysaccharide-Induced Inflammatory Responses via NF-κB/ERK-JNK MAPK/STAT3 Pathways. Mediators Inflamm 2022; 2022:6281892. [PMID: 35795403 PMCID: PMC9251077 DOI: 10.1155/2022/6281892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 05/19/2022] [Accepted: 06/11/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Magnoliae flos is the dried flower bud of Magnolia biondii and related plants. It has been used as a medicinal herb for the treatment of rhinitis, sinusitis, and sinus headaches. Nevertheless, the effects of Magnoliae flos in microbial infection or sepsis remain unclear. In this study, we investigated the anti-inflammatory effects of Magnoliae flos water extract (MF) in lipopolysaccharide- (LPS-) induced septic mice and LPS-stimulated RAW264.7 macrophages. Results. We found that MF reduced the mortality of LPS-challenged mice. Enzyme immunoassays and reverse transcription polymerase chain reaction analysis revealed that MF administration attenuated mRNA expression and protein production of proinflammatory mediators, including cyclooxygenase 2, inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-6. In parallel to these results in mice, pretreatment with MF suppressed the LPS-induced production of proinflammatory mediators in RAW264.7 macrophages. In addition, we found that MF exerted its suppressive effects by inhibiting the activation of the mitogen-activated protein kinase, nuclear factor-κB, and signal transducer and activator of transcription pathways at the protein level. Conclusion. MF could be a potential therapeutic agent for regulating excessive inflammatory responses in sepsis.
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Magoulopoulou A, Qian X, Pediatama Setiabudiawan T, Marco Salas S, Yokota C, Rottenberg ME, Nilsson M, Carow B. Spatial Resolution of Mycobacterium tuberculosis Bacteria and Their Surrounding Immune Environments Based on Selected Key Transcripts in Mouse Lungs. Front Immunol 2022; 13:876321. [PMID: 35663950 PMCID: PMC9157500 DOI: 10.3389/fimmu.2022.876321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Mycobacterium tuberculosis (Mtb) bacilli are the causative agent of tuberculosis (TB), a major killer of mankind. Although it is widely accepted that local interactions between Mtb and the immune system in the tuberculous granuloma determine whether the outcome of infection is controlled or disseminated, these have been poorly studied due to methodological constraints. We have recently used a spatial transcriptomic technique, in situ sequencing (ISS), to define the spatial distribution of immune transcripts in TB mouse lungs. To further contribute to the understanding of the immune microenvironments of Mtb and their local diversity, we here present two complementary automated bacteria-guided analysis pipelines. These position 33 ISS-identified immune transcripts in relation to single bacteria and bacteria clusters. The analysis was applied on new ISS data from lung sections of Mtb-infected C57BL/6 and C3HeB/FeJ mice. In lungs from C57BL/6 mice early and late post infection, transcripts that define inflammatory macrophages were enriched at subcellular distances to bacteria, indicating the activation of infected macrophages. In contrast, expression patterns associated to antigen presentation were enriched in non-infected cells at 12 weeks post infection. T-cell transcripts were evenly distributed in the tissue. In Mtb-infected C3HeB/FeJ mice, transcripts characterizing activated macrophages localized in apposition to small bacteria clusters, but not in organized granulomas. Despite differences in the susceptibility to Mtb, the transcript patterns found around small bacteria clusters of C3HeB/FeJ and C57BL/6 mice were similar. Altogether, the presented tools allow us to characterize in depth the immune cell populations and their activation that interact with Mtb in the infected lung.
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Affiliation(s)
- Anastasia Magoulopoulou
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
| | - Xiaoyan Qian
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
| | - Todia Pediatama Setiabudiawan
- Department of Microbiology, Tumor and Cell Biology and Centre for Tuberculosis Research, Karolinska Institutet, Solna, Sweden
| | - Sergio Marco Salas
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
| | - Chika Yokota
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
| | - Martin E Rottenberg
- Department of Microbiology, Tumor and Cell Biology and Centre for Tuberculosis Research, Karolinska Institutet, Solna, Sweden
| | - Mats Nilsson
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
| | - Berit Carow
- Department of Microbiology, Tumor and Cell Biology and Centre for Tuberculosis Research, Karolinska Institutet, Solna, Sweden
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31
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Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs. Physiol Rev 2022; 103:31-276. [DOI: 10.1152/physrev.00028.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
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Affiliation(s)
- Giuseppe Cirino
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece & Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece
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32
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Fungal-derived compounds and mycogenic nanoparticles with antimycobacterial activity: a review. SN APPLIED SCIENCES 2022. [DOI: 10.1007/s42452-022-05010-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
AbstractTuberculosis (TB) is a persistent lung infection caused by Mycobacterium tuberculosis. The disease is characterized by high mortality rates of over 1 million per year. Unfortunately, the potency and effectiveness of currently used anti-TB drugs is gradually decreasing due to the constant development of persistence and resistance by M. tuberculosis. The adverse side effects associated with current anti-TB drugs, along with anti-TB drug resistance, present an opportunity to bio-prospect novel potent anti-TB drugs from unique sources. Fundamentally, fungi are a rich source of bioactive secondary metabolites with valuable therapeutic potential. Enhancing the potency and effectiveness of fungal-based anti-TB drug leads by chemical synthesis and/or modification with nanomaterials, may result in the discovery of novel anti-TB drugs. In this review, the antimycobacterial activity of fungal-derived compounds and mycogenic nanoparticles are summarized. Numerous fungal-derived compounds as well as some mycogenic nanoparticles that exhibit strong antimycobacterial activity that is comparable to that of approved drugs, were found. If fully explored, fungi holds the promise to become key drivers in the generation of lead compounds in TB-drug discovery initiatives.
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33
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Stupar M, Furness J, De Voss CJ, Tan L, West NP. Two-component sensor histidine kinases of Mycobacterium tuberculosis: beacons for niche navigation. Mol Microbiol 2022; 117:973-985. [PMID: 35338720 PMCID: PMC9321153 DOI: 10.1111/mmi.14899] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/12/2022] [Accepted: 03/22/2022] [Indexed: 11/27/2022]
Abstract
Intracellular bacterial pathogens such as Mycobacterium tuberculosis are remarkably adept at surviving within a host, employing a variety of mechanisms to counteract host defenses and establish a protected niche. Constant surveying of the environment is key for pathogenic mycobacteria to discern their immediate location and coordinate the expression of genes necessary for adaptation. Two‐component systems efficiently perform this role, typically comprised of a transmembrane sensor kinase and a cytoplasmic response regulator. In this review, we describe the role of two‐component systems in bacterial pathogenesis, focusing predominantly on the role of sensor kinases of M. tuberculosis. We highlight important features of sensor kinases in mycobacterial infection, discuss ways in which these signaling proteins sense and respond to environments, and how this is attuned to their intracellular lifestyle. Finally, we discuss recent studies which have identified and characterized inhibitors of two‐component sensor kinases toward establishing a new strategy in anti‐mycobacterial therapy.
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Affiliation(s)
- Miljan Stupar
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, University of Queensland, Brisbane, 4072, Australia
| | - Juanelle Furness
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, University of Queensland, Brisbane, 4072, Australia
| | - Christopher J De Voss
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, University of Queensland, Brisbane, 4072, Australia
| | - Lendl Tan
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, University of Queensland, Brisbane, 4072, Australia
| | - Nicholas P West
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, University of Queensland, Brisbane, 4072, Australia
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Nasuno R, Iwai N, Takagi H. Development of a microtiter plate-based analysis method of nitric oxide dioxygenase activity. J GEN APPL MICROBIOL 2022; 68:38-41. [PMID: 35321969 DOI: 10.2323/jgam.2021.07.001] [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: 11/03/2022]
Abstract
Nitric oxide (NO) functions in cell protection or cell death, depending on its concentration. Therefore, regulation of the intracellular concentrations of NO by its degradation systems is important for cellular functions. One of the NO degrading enzymes, flavohemoglobin (FHb), which has NO dioxygenase (NOD) activity, is a promising target for antibiotics, based on the finding that FHb-deficient pathogens exhibited reduced host toxicity. Here, we developed a high-throughput method to measure the NOD activity. Our newly developed method could contribute to the screening of potential antibiotics with NOD inhibitory activity.
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Affiliation(s)
- Ryo Nasuno
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology
| | - Nozomi Iwai
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology
| | - Hiroshi Takagi
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology
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35
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Linge I, Tsareva A, Kondratieva E, Dyatlov A, Hidalgo J, Zvartsev R, Apt A. Pleiotropic Effect of IL-6 Produced by B-Lymphocytes During Early Phases of Adaptive Immune Responses Against TB Infection. Front Immunol 2022; 13:750068. [PMID: 35154093 PMCID: PMC8828505 DOI: 10.3389/fimmu.2022.750068] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/10/2022] [Indexed: 12/30/2022] Open
Abstract
The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.
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Affiliation(s)
- Irina Linge
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Anastasiya Tsareva
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Elena Kondratieva
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Alexander Dyatlov
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Juan Hidalgo
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ruslan Zvartsev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexander Apt
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
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36
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Cappelli EA, do Espírito Santo Cucinelli A, Simpson-Louredo L, Canellas MEF, Antunes CA, Burkovski A, da Silva JFR, Mattos-Guaraldi AL, Saliba AM, dos Santos LS. Insights of OxyR role in mechanisms of host-pathogen interaction of Corynebacterium diphtheriae. Braz J Microbiol 2022; 53:583-594. [PMID: 35169995 PMCID: PMC9151940 DOI: 10.1007/s42770-022-00710-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/08/2022] [Indexed: 02/01/2023] Open
Abstract
Corynebacterium diphtheriae, the leading causing agent of diphtheria, has been increasingly related to invasive diseases, including sepsis, endocarditis, pneumonia, and osteomyelitis. Oxidative stress defense is required not only for successful growth and survival under environmental conditions but also in the regulation of virulence mechanisms of human pathogenic species, by promoting mucosal colonization, survival, dissemination, and defense against the innate immune system. OxyR, functioning as a negative and/or positive transcriptional regulator, has been included among the major bacterial coordinators of antioxidant response. OxyR was first reported as a repressor of catalase expression in C. diphtheriae. However, the involvement of OxyR in C. diphtheriae pathogenesis remains unclear. Accordingly, this work aimed to investigate the role of OxyR in mechanisms of host-pathogen interaction of C. diphtheriae through the disruption of the OxyR of the diphtheria toxin (DT)-producing C. diphtheriae CDC-E8392 strain. The effects of OxyR gene disruption were analyzed through interaction assays with human epithelial cell lines (HEp-2 and pneumocytes A549) and by the induction of experimental infections in Caenorhabditis elegans nematodes and Swiss Webster mice. The OxyR disruption exerted influence on NO production and mechanism accountable for the expression of the aggregative-adherence pattern (AA) expressed by CDC-E8392 strain on human epithelial HEp-2 cells. Moreover, invasive potential and intracytoplasmic survival within HEp-2 cells, as well as the arthritogenic potential in mice, were found affected by the OxyR disruption. In conclusion, data suggest that OxyR is implicated in mechanisms of host-pathogen interaction of C. diphtheriae.
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Affiliation(s)
- Elisabete Alves Cappelli
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Andrezza do Espírito Santo Cucinelli
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Liliane Simpson-Louredo
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Maria Eurydice Freire Canellas
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Camila Azevedo Antunes
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil ,grid.5330.50000 0001 2107 3311Microbiology Division, Department of Biology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Andreas Burkovski
- grid.5330.50000 0001 2107 3311Microbiology Division, Department of Biology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Jemima Fuentes Ribeiro da Silva
- grid.412211.50000 0004 4687 5267Department of Histology and Embryology, Roberto Alcantara Gomes Biology Institute, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Ana Luíza Mattos-Guaraldi
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Alessandra Mattos Saliba
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Louisy Sanches dos Santos
- grid.412211.50000 0004 4687 5267Department of Microbiology, Immunology and Parasitology, Faculty of Medical Science, Rio de Janeiro State University, Rio de Janeiro, Brazil
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37
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Kim JK, Park EJ, Jo EK. Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection. Front Immunol 2022; 13:832015. [PMID: 35185924 PMCID: PMC8855927 DOI: 10.3389/fimmu.2022.832015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/13/2022] [Indexed: 12/29/2022] Open
Abstract
Immune metabolic regulation shapes the host-pathogen interaction during infection with Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB). Several immunometabolites generated by metabolic remodeling in macrophages are implicated in innate immune protection against Mtb infection by fine-tuning defensive pathways. Itaconate, produced by the mitochondrial enzyme immunoresponsive gene 1 (IRG1), has antimicrobial and anti-inflammatory effects, restricting intracellular mycobacterial growth. L-arginine, a component of the urea cycle, is critical for the synthesis of nitric oxide (NO) and is implicated in M1-mediated antimycobacterial responses in myeloid cells. L-citrulline, a by-product of NO production, contributes to host defense and generates L-arginine in myeloid cells. In arginase 1-expressing cells, L-arginine can be converted into ornithine, a polyamine precursor that enhances autophagy and antimicrobial protection against Mtb in Kupffer cells. Gamma-aminobutyric acid (GABA), a metabolite and neurotransmitter, activate autophagy to induce antimycobacterial host defenses. This review discusses the recent updates of the functions of the three metabolites in host protection against mycobacterial infection. Understanding the mechanisms by which these metabolites promote host defense will facilitate the development of novel host-directed therapeutics against Mtb and drug-resistant bacteria.
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Affiliation(s)
- Jin Kyung Kim
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Eun-Jin Park
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
- *Correspondence: Eun-Kyeong Jo,
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38
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Butucel E, Balta I, Ahmadi M, Dumitrescu G, Morariu F, Pet I, Stef L, Corcionivoschi N. Biocides as Biomedicines against Foodborne Pathogenic Bacteria. Biomedicines 2022; 10:biomedicines10020379. [PMID: 35203588 PMCID: PMC8962343 DOI: 10.3390/biomedicines10020379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 11/16/2022] Open
Abstract
Biocides are currently considered the first line of defense against foodborne pathogens in hospitals or food processing facilities due to the versatility and efficiency of their chemical active ingredients. Understanding the biological mechanisms responsible for their increased efficiency, especially when used against foodborne pathogens on contaminated surfaces and materials, represents an essential first step in the implementation of efficient strategies for disinfection as choosing an unsuitable product can lead to antibiocide resistance or antibiotic–biocide cross-resistance. This review describes these biological mechanisms for the most common foodborne pathogens and focuses mainly on the antipathogen effect, highlighting the latest developments based on in vitro and in vivo studies. We focus on biocides with inhibitory effects against foodborne bacteria (e.g., Escherichia spp., Klebsiella spp., Staphylococcus spp., Listeria spp., Campylobacter spp.), aiming to understand their biological mechanisms of action by looking at the most recent scientific evidence in the field.
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Affiliation(s)
- Eugenia Butucel
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast BT4 3SD, UK; (E.B.); (I.B.)
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
| | - Igori Balta
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast BT4 3SD, UK; (E.B.); (I.B.)
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
- Faculty of Animal Science and Biotechnologies, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Mirela Ahmadi
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
| | - Gabi Dumitrescu
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
| | - Florica Morariu
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
| | - Ioan Pet
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
| | - Lavinia Stef
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
- Correspondence: (L.S.); (N.C.)
| | - Nicolae Corcionivoschi
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast BT4 3SD, UK; (E.B.); (I.B.)
- Faculty of Bioengineering of Animal Resources, Banat University of Animal Sciences and Veterinary Medicine—King Michael I of Romania, 300645 Timisoara, Romania; (M.A.); (G.D.); (F.M.); (I.P.)
- Correspondence: (L.S.); (N.C.)
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Del Rosario RCH, Poschmann J, Lim C, Cheng CY, Kumar P, Riou C, Ong ST, Gerges S, Hajan HS, Kumar D, Marzuki M, Lu X, Lee A, Wijaya GC, Rayan NA, Zhuang Z, Du Bruyn E, Chee CBE, Lee B, Lum J, Zolezzi F, Poidinger M, Rotzschke O, Khor CC, Wilkinson RJ, Wang YT, Chandy GK, De Libero G, Singhal A, Prabhakar S. Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection. Nat Microbiol 2022; 7:312-326. [PMID: 35102304 PMCID: PMC9439955 DOI: 10.1038/s41564-021-01049-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022]
Abstract
Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.
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Affiliation(s)
- Ricardo C H Del Rosario
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jeremie Poschmann
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Inserm, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, ITUN, Nantes, France
| | - Carey Lim
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | | | - Pavanish Kumar
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Catherine Riou
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Seow Theng Ong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Sherif Gerges
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Hajira Shreen Hajan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Dilip Kumar
- Inserm, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, ITUN, Nantes, France
| | - Mardiana Marzuki
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | - Xiaohua Lu
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Andrea Lee
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | - Giovani Claresta Wijaya
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Nirmala Arul Rayan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Zhong Zhuang
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Elsa Du Bruyn
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | | | - Bernett Lee
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Josephine Lum
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | | | | | - Olaf Rotzschke
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Robert J Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Infectious Disease, Imperial College, London, UK
- The Francis Crick Institute, London, UK
| | - Yee T Wang
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore, Singapore
| | - George K Chandy
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Gennaro De Libero
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Amit Singhal
- Singapore Immunology Network, A*STAR, Singapore, Singapore.
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
| | - Shyam Prabhakar
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
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Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis. Bioorg Med Chem 2022; 53:116506. [PMID: 34890996 DOI: 10.1016/j.bmc.2021.116506] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022]
Abstract
Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure-activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC50 2.0 ± 1.1 and 2.3 ± 1.1 µM, respectively). Moreover, these compounds were active against the hypervirulent clinical Mtb strain M299, in bacterial culture, especially 16, 28 and 29, and in extracellular clumps, highlighting 29, with MIC50 5.6 ± 1.2 µM. Regarding inflammation, they inhibited NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. In silico studies were carried out suggesting that these five compounds could be administered by oral route and have low toxicological effects when compared to rifampicin. In conclusion, our data show that, at least, thiourea derivatives 16, 28 and 29 are promising antimycobacterial and anti-inflammatory agents, and candidates for further prospective studies aiming new anti-TB drugs, that can be used on a dual approach for the treatment of severe TB cases associated with exacerbated inflammation.
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Zhang S, Liu Y, Zhou X, Ou M, Xiao G, Li F, Wang Z, Wang Z, Liu L, Zhang G. Sirtuin 7 Regulates Nitric Oxide Production and Apoptosis to Promote Mycobacterial Clearance in Macrophages. Front Immunol 2021; 12:779235. [PMID: 34925356 PMCID: PMC8678072 DOI: 10.3389/fimmu.2021.779235] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/18/2021] [Indexed: 01/14/2023] Open
Abstract
The host immune system plays a pivotal role in the containment of Mycobacterium tuberculosis (Mtb) infection, and host-directed therapy (HDT) is emerging as an effective strategy to treat tuberculosis (TB), especially drug-resistant TB. Previous studies revealed that expression of sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, was downregulated in macrophages after Mycobacterial infection. Inhibition of SIRT7 with the pan-sirtuin family inhibitor nicotinamide (NAM), or by silencing SIRT7 expression, promoted intracellular growth of Mtb and restricted the generation of nitric oxide (NO). Addition of the exogenous NO donor SNAP abrogated the increased bacterial burden in NAM-treated or SIRT7-silenced macrophages. Furthermore, SIRT7-silenced macrophages displayed a lower frequency of early apoptotic cells after Mycobacterial infection, and this could be reversed by providing exogenous NO. Overall, this study clarified a SIRT7-mediated protective mechanism against Mycobacterial infection through regulation of NO production and apoptosis. SIRT7 therefore has potential to be exploited as a novel effective target for HDT of TB.
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Affiliation(s)
- Su Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yaya Liu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xuefeng Zhou
- School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Min Ou
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Guohui Xiao
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Fang Li
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Zhongyuan Wang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Zhaoqin Wang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Lei Liu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Guoliang Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
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Abukhalid N, Islam S, Ndzeidze R, Bermudez LE. Mycobacterium avium Subsp. hominissuis Interactions with Macrophage Killing Mechanisms. Pathogens 2021; 10:1365. [PMID: 34832521 PMCID: PMC8623537 DOI: 10.3390/pathogens10111365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 11/16/2022] Open
Abstract
Non-tuberculosis mycobacteria (NTM) are ubiquitously found throughout the environment. NTM can cause respiratory infections in individuals with underlying lung conditions when inhaled, or systemic infections when ingested by patients with impaired immune systems. Current therapies can be ineffective at treating NTM respiratory infections, even after a long course or with multidrug treatment regimens. NTM, such as Mycobacterium avium subspecies hominissuis (M. avium), is an opportunistic pathogen that shares environments with ubiquitous free-living amoeba and other environmental hosts, possibly their evolutionary hosts. It is highly likely that interactions between M. avium and free-living amoeba have provided selective pressure on the bacteria to acquire survival mechanisms, which are also used against predation by macrophages. In macrophages, M. avium resides inside phagosomes and has been shown to exit it to infect other cells. M. avium's adaptation to the hostile intra-phagosomal environment is due to many virulence mechanisms. M. avium is able to switch the phenotype of the macrophage to be anti-inflammatory (M2). Here, we have focused on and discussed the bacterial defense mechanisms associated with the intra-phagosome phase of infection. M. avium possesses a plethora of antioxidant enzymes, including the superoxide dismutases, catalase and alkyl hydroperoxide reductase. When these defenses fail or are overtaken by robust oxidative burst, many other enzymes exist to repair damage incurred on M. avium proteins, including thioredoxin/thioredoxin reductase. Finally, M. avium has several oxidant sensors that induce transcription of antioxidant enzymes, oxidation repair enzymes and biofilm- promoting genes. These expressions induce physiological changes that allow M. avium to survive in the face of leukocyte-generated oxidative stress. We will discuss the strategies used by M. avium to infect human macrophages that evolved during its evolution from free-living amoeba. The more insight we gain about M. avium's mode of pathogenicity, the more targets we can have to direct new anti-virulence therapies toward.
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Affiliation(s)
- Norah Abukhalid
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA; (N.A.); (S.I.); (R.N.)
| | - Sabrina Islam
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA; (N.A.); (S.I.); (R.N.)
| | - Robert Ndzeidze
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA; (N.A.); (S.I.); (R.N.)
| | - Luiz E. Bermudez
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA; (N.A.); (S.I.); (R.N.)
- Department of Microbiology, College of Science, Oregon State University, Corvallis, OR 97331, USA
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Nandanwar N, Gibson JE, Neely MN. Growth medium and nitric oxide alter Mycobacterium abscessus morphotype and virulence. Microbiol Res 2021; 253:126887. [PMID: 34628130 DOI: 10.1016/j.micres.2021.126887] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 10/20/2022]
Abstract
Mycobacterium abscessus complex (MABC) infections cause significant morbidity and mortality among patients with chronic lung disease, like cystic fibrosis. MABC exists in smooth (S) and rough (R) morphotypes, but triggers of morphotype switching and associated pathogenicity or antimicrobial susceptibility are poorly understood. We demonstrate that M. abscessus subspecies abscessus (Mab), massiliense (Mms), and bolletii (Mbl) cultured in Middlebrook (MB) broth exhibit S morphotype, whereas the bacteria grown in Luria Bertani (LB) broth adopt the R morphotype, characterized by low glycopeptidolipid (GPL) expression. The components of broth that mediate this selection are complex, with albumin supplementation promoting growth of S morphotype, but not sufficient for complete selection. Consistent with the findings of other groups, R forms of Mab, Mms and Mbl selected by LB broth were internalized in RAW 264.7 macrophages with higher efficiency than S. Intracellular survival of broth-selected organisms was variable and was higher for S Mab, but lower for S Mms and Mbl. It is proposed that growth in R morphotype is induced during stress conditions, such as nutrient poor environments or during inflammation. One key component of inflammation is release of nitric oxide. We demonstrated that a nitric oxide donor (DETA-NONOate) appears to induce growth in an R morphotype, as indicated by reduced GPL expression of Mab. Mab treated with DETA-NONOate also enhanced susceptibility to azithromycin at sub-MIC concentrations. In conclusion, morphotype and macrophage intracellular bacterial load of MABC subspecies can be manipulated by growing the bacteria in different culture conditions. Nitric oxide may also drive morphotype selection and enhanced azithromycin activity against Mab and macrophage killing.
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Affiliation(s)
- Nishant Nandanwar
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Joy E Gibson
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Michael N Neely
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
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Stimulation of Toll-Like Receptor 3 Diminishes Intracellular Growth of Salmonella Typhimurium by Enhancing Autophagy in Murine Macrophages. Metabolites 2021; 11:metabo11090602. [PMID: 34564417 PMCID: PMC8466172 DOI: 10.3390/metabo11090602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 12/03/2022] Open
Abstract
The Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative Gram-negative bacterium that causes acute gastroenteritis and food poisoning. S. Typhimurium can survive within macrophages that are able to initiate the innate immune response after recognizing bacteria via various pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs). In this study, we investigated the effects and molecular mechanisms by which agonists of endosomal TLRs—especially TLR3—contribute to controlling S. Typhimurium infection in murine macrophages. Treatment with polyinosinic:polycytidylic acid (poly(I:C))—an agonist of TLR3—significantly suppressed intracellular bacterial growth by promoting intracellular ROS production in S. Typhimurium-infected cells. Pretreatment with diphenyleneiodonium (DPI)—an NADPH oxidase inhibitor—reduced phosphorylated MEK1/2 levels and restored intracellular bacterial growth in poly(I:C)-treated cells during S. Typhimurium infection. Nitric oxide (NO) production increased through the NF-κB-mediated signaling pathway in poly(I:C)-treated cells during S. Typhimurium infection. Intracellular microtubule-associated protein 1A/1B-light chain 3 (LC3) levels were increased in poly(I:C)-treated cells; however, they were decreased in cells pretreated with 3-methyladenine (3-MA)—a commonly used inhibitor of autophagy. These results suggest that poly(I:C) induces autophagy and enhances ROS production via MEK1/2-mediated signaling to suppress intracellular bacterial growth in S. Typhimurium-infected murine macrophages, and that a TLR3 agonist could be developed as an immune enhancer to protect against S. Typhimurium infection.
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Mariappan V, Vellasamy KM, Barathan M, Girija ASS, Shankar EM, Vadivelu J. Hijacking of the Host's Immune Surveillance Radars by Burkholderia pseudomallei. Front Immunol 2021; 12:718719. [PMID: 34456925 PMCID: PMC8384953 DOI: 10.3389/fimmu.2021.718719] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/12/2021] [Indexed: 11/20/2022] Open
Abstract
Burkholderia pseudomallei (B. pseudomallei) causes melioidosis, a potentially fatal disease for which no licensed vaccine is available thus far. The host-pathogen interactions in B. pseudomallei infection largely remain the tip of the iceberg. The pathological manifestations are protean ranging from acute to chronic involving one or more visceral organs leading to septic shock, especially in individuals with underlying conditions similar to COVID-19. Pathogenesis is attributed to the intracellular ability of the bacterium to ‘step into’ the host cell’s cytoplasm from the endocytotic vacuole, where it appears to polymerize actin filaments to spread across cells in the closer vicinity. B. pseudomallei effectively evades the host’s surveillance armory to remain latent for prolonged duration also causing relapses despite antimicrobial therapy. Therefore, eradication of intracellular B. pseudomallei is highly dependent on robust cellular immune responses. However, it remains ambiguous why certain individuals in endemic areas experience asymptomatic seroconversion, whereas others succumb to sepsis-associated sequelae. Here, we propose key insights on how the host’s surveillance radars get commandeered by B. pseudomallei.
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Affiliation(s)
- Vanitha Mariappan
- Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Kumutha Malar Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - A S Smiline Girija
- Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Esaki M Shankar
- Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
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Osei-Wusu S, Otchere ID, Morgan P, Musah AB, Siam IM, Asandem D, Afum T, Asare P, Asante-Poku A, Kusi KA, Gagneux S, Yeboah-Manu D. Genotypic and phenotypic diversity of Mycobacterium tuberculosis complex genotypes prevalent in West Africa. PLoS One 2021; 16:e0255433. [PMID: 34437584 PMCID: PMC8389432 DOI: 10.1371/journal.pone.0255433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022] Open
Abstract
Findings from previous comparative genomics studies of the Mycobacterium tuberculosis complex (MTBC) suggest genomic variation among the genotypes may have phenotypic implications. We investigated the diversity in the phenotypic profiles of the main prevalent MTBC genotypes in West Africa. Thirty-six whole genome sequenced drug susceptible MTBC isolates belonging to lineages 4, 5 and 6 were included in this study. The isolates were phenotypically characterized for urease activity, tween hydrolysis, Thiophen-2-Carboxylic Acid Hydrazide (TCH) susceptibility, nitric oxide production, and growth rate in both liquid (7H9) and solid media (7H11 and Löwenstein-Jensen (L-J)). Lineage 4 isolates showed the highest growth rate in both liquid (p = 0.0003) and on solid (L-J) media supplemented with glycerol (p<0.001) or pyruvate (p = 0.005). L6 isolates optimally utilized pyruvate compared to glycerol (p<0.001), whereas L5 isolates grew similarly on both media (p = 0.05). Lineage 4 isolates showed the lowest average time to positivity (TTP) (p = 0.01; Average TTP: L4 = 15days, L5 = 16.7days, L6 = 29.7days) and the highest logCFU/mL (p = 0.04; average logCFU/mL L4 = 5.9, L5 = 5.0, L6 = 4.4) on 7H11 supplemented with glycerol, but there was no significant difference in growth on 7H11 supplemented with pyruvate (p = 0.23). The highest release of nitrite was recorded for L5 isolates, followed by L4 and L6 isolates. However, the reverse was observed in the urease activity for the lineages. All isolates tested were resistant to TCH except for one L6 isolate. Comparative genomic analyses revealed several mutations that might explain the diverse phenotypic profiles of these isolates. Our findings showed significant phenotypic diversity among the MTBC lineages used for this study.
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Affiliation(s)
- Stephen Osei-Wusu
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Isaac Darko Otchere
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Portia Morgan
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Abdul Basit Musah
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
| | - Ishaque Mintah Siam
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
| | - Diana Asandem
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Theophilus Afum
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
| | - Prince Asare
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Adwoa Asante-Poku
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
| | - Kwadwo Asamoah Kusi
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
| | - Sebastien Gagneux
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Dorothy Yeboah-Manu
- Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
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Nitric Oxide-Dependent Electron Transport Chain Inhibition by the Cytochrome bc1 Inhibitor and Pretomanid Combination Kills Mycobacterium tuberculosis. Antimicrob Agents Chemother 2021; 65:e0095621. [PMID: 34152815 DOI: 10.1128/aac.00956-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Mycobacterium tuberculosis, the causative agent of human tuberculosis, harbors a branched electron transport chain, preventing the bactericidal action of cytochrome bc1 inhibitors (e.g., TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. The TB47 and PMD combination quickly abolished the light emission of luminescent bacilli, as was the case for the combination of TB47 and aurachin D, a putative cytochrome bd inhibitor. The TB47 and PMD combination inhibited M. tuberculosis oxygen consumption, decreased ATP levels, and had a delayed bactericidal effect. The NO scavenger carboxy-PTIO prevented the bactericidal activity of the drug combination, suggesting the requirement for NO. In addition, cytochrome bc1 inhibitors were largely bactericidal when administered with DETA NONOate, another NO donor. Proteomic analysis revealed that the cotreated bacilli had a compromised expression of the dormancy regulon proteins, PE/PPE proteins, and proteins required for the biosynthesis of several cofactors, including mycofactocin. Some of these proteomic changes, e.g., the impaired dormancy regulon induction, were attributed to PMD. In conclusion, combination of cytochrome bc1 inhibitors with PMD inhibited M. tuberculosis respiration and killed the bacilli. The activity of cytochrome bc1 inhibitors can be greatly enhanced by NO donors. Monitoring of luminescence may be further exploited to screen cytochrome bd inhibitors.
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Wang X, Mehra S, Kaushal D, Veazey RS, Xu H. Abnormal Tryptophan Metabolism in HIV and Mycobacterium tuberculosis Infection. Front Microbiol 2021; 12:666227. [PMID: 34262540 PMCID: PMC8273495 DOI: 10.3389/fmicb.2021.666227] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022] Open
Abstract
Host metabolism has recently gained more attention for its roles in physiological functions and pathologic conditions. Of these, metabolic tryptophan disorders generate a pattern of abnormal metabolites that are implicated in various diseases. Here, we briefly highlight the recent advances regarding abnormal tryptophan metabolism in HIV and Mycobacterium tuberculosis infection and discuss its potential impact on immune regulation, disease progression, and neurological disorders. Finally, we also discuss the potential for metabolic tryptophan interventions toward these infectious diseases.
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Affiliation(s)
- Xiaolei Wang
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, United States
| | - Smriti Mehra
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, United States
| | - Deepak Kaushal
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Ronald S. Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, United States
| | - Huanbin Xu
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, United States
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Porrini C, Ramarao N, Tran SL. Dr. NO and Mr. Toxic - the versatile role of nitric oxide. Biol Chem 2021; 401:547-572. [PMID: 31811798 DOI: 10.1515/hsz-2019-0368] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/04/2019] [Indexed: 12/25/2022]
Abstract
Nitric oxide (NO) is present in various organisms from humans, to plants, fungus and bacteria. NO is a fundamental signaling molecule implicated in major cellular functions. The role of NO ranges from an essential molecule to a potent mediator of cellular damages. The ability of NO to react with a broad range of biomolecules allows on one hand its regulation and a gradient concentration and on the other hand to exert physiological as well as pathological functions. In humans, NO is implicated in cardiovascular homeostasis, neurotransmission and immunity. However, NO can also contribute to cardiovascular diseases (CVDs) or septic shock. For certain denitrifying bacteria, NO is part of their metabolism as a required intermediate of the nitrogen cycle. However, for other bacteria, NO is toxic and harmful. To survive, those bacteria have developed processes to resist this toxic effect and persist inside their host. NO also contributes to maintain the host/microbiota homeostasis. But little is known about the impact of NO produced during prolonged inflammation on microbiota integrity, and some pathogenic bacteria take advantage of the NO response to colonize the gut over the microbiota. Taken together, depending on the environmental context (prolonged production, gradient concentration, presence of partners for interaction, presence of oxygen, etc.), NO will exert its beneficial or detrimental function. In this review, we highlight the dual role of NO for humans, pathogenic bacteria and microbiota, and the mechanisms used by each organism to produce, use or resist NO.
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Affiliation(s)
- Constance Porrini
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Nalini Ramarao
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Seav-Ly Tran
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
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Ogongo P, Tezera LB, Ardain A, Nhamoyebonde S, Ramsuran D, Singh A, Ng’oepe A, Karim F, Naidoo T, Khan K, Dullabh KJ, Fehlings M, Lee BH, Nardin A, Lindestam Arlehamn CS, Sette A, Behar SM, Steyn AJ, Madansein R, Kløverpris HN, Elkington PT, Leslie A. Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung. J Clin Invest 2021; 131:142014. [PMID: 33848273 PMCID: PMC8121523 DOI: 10.1172/jci142014] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue-resident memory T cells (Trms) are superior at controlling many pathogens, including Mycobacterium tuberculosis (M. tuberculosis), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct CD4+ and CD8+ Trm-like clusters within TB-diseased lung tissue that were functional and enriched for IL-17-producing cells. M. tuberculosis-specific CD4+ T cells producing TNF-α, IL-2, and IL-17 were highly expanded in the lung compared with matched blood samples, in which IL-17+ cells were largely absent. Strikingly, the frequency of M. tuberculosis-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1β levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and was associated with increased NO production. Taken together, these data support an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells in the immune control of M. tuberculosis in the human lung.
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Affiliation(s)
- Paul Ogongo
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya
| | - Liku B. Tezera
- National Institute for Health Research Southampton Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, and
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Amanda Ardain
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Shepherd Nhamoyebonde
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | | | - Alveera Singh
- Africa Health Research Institute, Durban, South Africa
| | | | - Farina Karim
- Africa Health Research Institute, Durban, South Africa
| | - Taryn Naidoo
- Africa Health Research Institute, Durban, South Africa
| | - Khadija Khan
- Africa Health Research Institute, Durban, South Africa
| | - Kaylesh J. Dullabh
- Department of Cardiothoracic Surgery, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | | | | | | | | | - Alessandro Sette
- La Jolla Institute for Immunology, La Jolla, California, USA
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Samuel M. Behar
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Adrie J.C. Steyn
- Africa Health Research Institute, Durban, South Africa
- Department of Microbiology and
- Center for AIDS Research and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rajhmun Madansein
- Department of Cardiothoracic Surgery, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Henrik N. Kløverpris
- Africa Health Research Institute, Durban, South Africa
- Division of Infection and Immunity, University College London, London, United Kingdom
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Paul T. Elkington
- National Institute for Health Research Southampton Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, and
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Alasdair Leslie
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Division of Infection and Immunity, University College London, London, United Kingdom
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