The Rough Morphotype of Mycobacterium abscessus Enhances Its Virulence Through ROS/p65/NLRP3/GSDMD-Mediated Macrophage Pyroptosis
Jingren Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorJuan Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorAnqi Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorZhili Tan
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorJunsheng Fan
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorSiyuan He
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorQi Guo
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorCorresponding Author
Liyun Xu
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
Correspondence:
Liyun Xu ([email protected])
Haiqing Chu ([email protected])
Search for more papers by this authorCorresponding Author
Haiqing Chu
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
Correspondence:
Liyun Xu ([email protected])
Haiqing Chu ([email protected])
Search for more papers by this authorJingren Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorJuan Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorAnqi Li
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorZhili Tan
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorJunsheng Fan
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorSiyuan He
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorQi Guo
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Search for more papers by this authorCorresponding Author
Liyun Xu
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
Correspondence:
Liyun Xu ([email protected])
Haiqing Chu ([email protected])
Search for more papers by this authorCorresponding Author
Haiqing Chu
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
School of Medicine, Tongji University, Shanghai, China
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
Correspondence:
Liyun Xu ([email protected])
Haiqing Chu ([email protected])
Search for more papers by this authorABSTRACT
The rough morphotype of Mycobacterium abscessus exhibits significantly higher virulence compared to the smooth morphotype, yet the underlying molecular mechanisms remain incompletely understood. Pyroptosis in macrophages plays a pivotal role in lung tissue damage; however, its specific involvement in Mycobacterium abscessus infection remains to be fully clarified. In this study, we identified that the rough morphotype of Mycobacterium abscessus upregulates the ROS/p65/NLRP3/GSDMD signalling pathway, thereby mediating pyroptosis in THP-1-derived macrophages. This heightened ability to induce macrophage pyroptosis is attributed to the bacterium's capacity to sustain intracellular viability and proliferation. These findings offer valuable insights into the virulence mechanisms of Mycobacterium abscessus and provide a foundation for future therapeutic interventions.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
Filename | Description |
---|---|
cep70034-sup-0001-FigureS1.tifTIFF image, 80.9 KB |
Figure S1. The total CFU count of M. abscessus within macrophages at 48 h post-infection. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1K. Rüger, A. Hampel, S. Billig, N. Rücker, S. Suerbaum, and F. C. Bange, “Characterization of Rough and Smooth Morphotypes of Mycobacterium abscessus Isolates From Clinical Specimens,” Journal of Clinical Microbiology 52 (2014): 244–250.
- 2G. Clary, S. J. Sasindran, N. Nesbitt, et al., “Mycobacterium abscessus Smooth and Rough Morphotypes Form Antimicrobial-Tolerant Biofilm Phenotypes but Are Killed by Acetic Acid,” Antimicrobial Agents and Chemotherapy 62 (2018): e01782-17.
- 3M. C. Muñoz-Egea, A. Akir, and J. Esteban, “Mycobacterium Biofilms,” Biofilms 5 (2023): 100107.
- 4B. Li, M. Ye, L. Zhao, et al., “Glycopeptidolipid Genotype Correlates With the Severity of Mycobacterium abscessus Lung Disease,” Journal of Infectious Diseases 221 (2020): S257–s262.
- 5W. Hedin, G. Fröberg, K. Fredman, et al., “A Rough Colony Morphology of Mycobacterium Abscessus Is Associated With Cavitary Pulmonary Disease and Poor Clinical Outcome,” Journal of Infectious Diseases 227 (2023): 820–827.
- 6A. Pawlik, G. Garnier, M. Orgeur, et al., “Identification and Characterization of the Genetic Changes Responsible for the Characteristic Smooth-To-Rough Morphotype Alterations of Clinically Persistent Mycobacterium abscessus,” Molecular Microbiology 90 (2013): 612–629.
- 7J. Shi, W. Gao, and F. Shao, “Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death,” Trends in Biochemical Sciences 42 (2017): 245–254.
- 8M. Li, Y. Liu, X. Nie, et al., “S100A4 Promotes BCG-Induced Pyroptosis of Macrophages by Activating the NF-κB/NLRP3 Inflammasome Signaling Pathway,” International Journal of Molecular Sciences 24 (2023): 12709.
- 9Z. Qu, J. Zhou, Y. Zhou, et al., “Mycobacterial EST12 Activates a RACK1-NLRP3-Gasdermin D Pyroptosis-IL-1β Immune Pathway,” Science Advances 6 (2020): 6.
10.1126/sciadv.aba4733 Google Scholar
- 10K. Dheda, H. Booth, J. F. Huggett, M. A. Johnson, A. Zumla, and G. A. Rook, “Lung Remodeling in Pulmonary Tuberculosis,” Journal of Infectious Diseases 192 (2005): 1201–1209.
- 11L. Srinivasan, S. Ahlbrand, and V. Briken, “Interaction of Mycobacterium tuberculosis With Host Cell Death Pathways,” Cold Spring Harbor Perspectives in Medicine 4 (2014): a022459.
- 12R. L. Hunter, J. K. Actor, S. A. Hwang, V. Karev, and C. Jagannath, “Pathogenesis of Post Primary Tuberculosis: Immunity and Hypersensitivity in the Development of Cavities,” Annals of Clinical and Laboratory Science 44 (2014): 365–387.
- 13S. D. Lawn and A. I. Zumla, “Tuberculosis,” Lancet 378 (2011): 57–72.
- 14J. Y. Kam, E. Hortle, E. Krogman, et al., “Rough and Smooth Variants of Mycobacterium abscessus Are Differentially Controlled by Host Immunity During Chronic Infection of Adult Zebrafish,” Nature Communications 13 (2022): 952.
- 15E. Catherinot, J. Clarissou, G. Etienne, et al., “Hypervirulence of a Rough Variant of the Mycobacterium abscessus Type Strain,” Infection and Immunity 75 (2007): 1055–1058.
- 16H. Blaser, C. Dostert, T. W. Mak, and D. Brenner, “TNF and ROS Crosstalk in Inflammation,” Trends in Cell Biology 26 (2016): 249–261.
- 17N. Ganguly, P. H. Giang, C. Gupta, et al., “Mycobacterium tuberculosis Secretory Proteins CFP-10, ESAT-6 and the CFP10:ESAT6 Complex Inhibit Lipopolysaccharide-Induced NF-kappaB Transactivation by Downregulation of Reactive Oxidative Species (ROS) Production,” Immunology and Cell Biology 86 (2008): 98–106.
- 18M. J. Morgan and Z. G. Liu, “Crosstalk of Reactive Oxygen Species and NF-κB Signaling,” Cell Research 21 (2011): 103–115.
- 19P. Andrieux, C. Chevillard, E. Cunha-Neto, and J. P. S. Nunes, “Mitochondria as a Cellular Hub in Infection and Inflammation,” International Journal of Molecular Sciences 22 (2021): 11338.
- 20L. Ma, Y. Cheng, X. Feng, et al., “A Janus-ROS Healing System Promoting Infectious Bone Regeneration via Sono-Epigenetic Modulation,” Advanced Materials 36 (2024): e2307846.
- 21H. M. Lee, J. Kang, S. J. Lee, and E. K. Jo, “Microglial Activation of the NLRP3 Inflammasome by the Priming Signals Derived From Macrophages Infected With Mycobacteria,” Glia 61 (2013): 441–452.
- 22C. Xu, Y. Yue, and S. Xiong, “Mycobacterium Tuberculosis Rv0928 Protein Facilitates Macrophage Control of Mycobacterium Infection by Promoting Mitochondrial Intrinsic Apoptosis and ROS-Mediated Inflammation,” Frontiers in Microbiology 14 (2023): 1291358.
- 23W. Liu, Y. Peng, Y. Yin, Z. Zhou, W. Zhou, and Y. Dai, “The Involvement of NADPH Oxidase-Mediated ROS in Cytokine Secretion From Macrophages Induced by Mycobacterium tuberculosis ESAT-6,” Inflammation 37 (2014): 880–892.
- 24G. Raghu, M. Berk, P. A. Campochiaro, et al., “The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress,” Current Neuropharmacology 19 (2021): 1202–1224.
- 25G. Weiss and U. E. Schaible, “Macrophage Defense Mechanisms Against Intracellular Bacteria,” Immunological Reviews 264 (2015): 182–203.
- 26R. P. Wilkie-Grantham, N. J. Magon, D. T. Harwood, et al., “Myeloperoxidase-Dependent Lipid Peroxidation Promotes the Oxidative Modification of Cytosolic Proteins in Phagocytic Neutrophils,” Journal of Biological Chemistry 290 (2015): 9896–9905.
- 27S. Dupré-Crochet, M. Erard, and O. Nüβe, “ROS Production in Phagocytes: Why, When, and Where?,” Journal of Leukocyte Biology 94 (2013): 657–670.
- 28C. Zhou, W. Zhong, J. Zhou, et al., “Monitoring Autophagic Flux by an Improved Tandem Fluorescent-Tagged LC3 (mTagRFP-mWasabi-LC3) Reveals That High-Dose Rapamycin Impairs Autophagic Flux in Cancer Cells,” Autophagy 8 (2012): 1215–1226.
- 29J. Adjemian, K. N. Olivier, A. E. Seitz, S. M. Holland, and D. R. Prevots, “Prevalence of Nontuberculous Mycobacterial Lung Disease in U.S. Medicare Beneficiaries,” American Journal of Respiratory and Critical Care Medicine 185 (2012): 881–886.
- 30K. Morimoto, K. Iwai, K. Uchimura, et al., “A Steady Increase in Nontuberculous Mycobacteriosis Mortality and Estimated Prevalence in Japan,” Annals of the American Thoracic Society 11 (2014): 1–8.
- 31W. J. Koh, B. Chang, B. H. Jeong, et al., “Increasing Recovery of Nontuberculous Mycobacteria From Respiratory Specimens Over a 10-Year Period in a Tertiary Referral Hospital in South Korea,” Tuberculosis and Respiratory Diseases 75 (2013): 199–204.
- 32L. J. Caverly, S. M. Caceres, C. Fratelli, et al., “Mycobacterium abscessus Morphotype Comparison in a Murine Model,” PLoS One 10 (2015): e0117657.
- 33F. J. Roca and L. Ramakrishnan, “TNF Dually Mediates Resistance and Susceptibility to Mycobacteria via Mitochondrial Reactive Oxygen Species,” Cell 153 (2013): 521–534.
- 34F. J. Roca, L. J. Whitworth, S. Redmond, A. A. Jones, and L. Ramakrishnan, “TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis Through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit,” Cell 178 (2019): 1344–1361.e11.
- 35T. S. Kim, Y. B. Jin, Y. S. Kim, et al., “SIRT3 Promotes Antimycobacterial Defenses by Coordinating Mitochondrial and Autophagic Functions,” Autophagy 15 (2019): 1356–1375.
- 36S. R. Choi, G. A. Talmon, B. E. Britigan, and P. Narayanasamy, “Nanoparticulate β-Cyclodextrin With Gallium Tetraphenylporphyrin Demonstrates In Vitro and In Vivo Antimicrobial Efficacy Against Mycobacteroides Abscessus and Mycobacterium avium,” ACS Infectious Diseases 7 (2021): 2299–2309.
- 37B. R. Kim, B. J. Kim, Y. H. Kook, and B. J. Kim, “Mycobacterium abscessus Infection Leads to Enhanced Production of Type 1 Interferon and NLRP3 Inflammasome Activation in Murine Macrophages via Mitochondrial Oxidative Stress,” PLoS Pathogens 16 (2020): e1008294.
- 38R. Chai, Z. Ye, W. Xue, et al., “Tanshinone IIA Inhibits Cardiomyocyte Pyroptosis Through TLR4/NF-κB p65 Pathway After Acute Myocardial Infarction,” Frontiers in Cell and Development Biology 11 (2023): 1252942.
- 39X. Tian, Y. Zeng, Q. Tu, et al., “Butyrate Alleviates Renal Fibrosis in CKD by Regulating NLRP3-Mediated Pyroptosis via the STING/NF-κB/p65 Pathway,” International Immunopharmacology 124 (2023): 111010.
- 40T. Li, H. Sun, Y. Li, et al., “Downregulation of Macrophage Migration Inhibitory Factor Attenuates NLRP3 Inflammasome Mediated Pyroptosis in Sepsis-Induced AKI,” Cell Death Discovery 8 (2022): 61.
- 41W. M. Nauseef, “How Human Neutrophils Kill and Degrade Microbes: An Integrated View,” Immunological Reviews 219 (2007): 88–102.
- 42C. C. Winterbourn, A. J. Kettle, and M. B. Hampton, “Reactive Oxygen Species and Neutrophil Function,” Annual Review of Biochemistry 85 (2016): 765–792.
- 43D. Wong, H. Bach, J. Sun, Z. Hmama, and Y. Av-Gay, “Mycobacterium tuberculosis Protein Tyrosine Phosphatase (PtpA) Excludes Host Vacuolar-H+-ATPase to Inhibit Phagosome Acidification,” Proceedings of the National Academy of Sciences of the United States of America 108 (2011): 19371–19376.
- 44J. Fan, Y. Jia, S. He, et al., “GlnR Activated Transcription of Nitrogen Metabolic Pathway Genes Facilitates Biofilm Formation by Mycobacterium abscessus,” International Journal of Antimicrobial Agents 63 (2024): 107025.
- 45B. Li, S. He, Z. Tan, et al., “Impaired ESX-3 Induces Bedaquiline Persistence in Mycobacterium Abscessus Growing Under Iron-Limited Conditions,” Small Methods 7 (2023): e2300183.