Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Datta, Debika; Khatri, Preeti; Singh, Abhilasha; Saha, Dhira Rani; Verma, Gaurav; Rajagopal, Raman; Mazumder, Shibnath

doi:10.1038/s41420-018-0034-9

Cited by 27 publications

(24 citation statements)

References 54 publications

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“…Bacterial cords can withstand phagocytosis by macrophages which further exacerbates uncontrolled bacterial multiplication and ultimately results in abscess formation, tissue damage and larval death. This is supported by recent findings indicating that caspase-mediated apoptosis of catfish macrophages occurs rapidly after infection with M. fortuitum (Datta et al, 2018 ). Thus, one can envisage a similar scenario where apoptosis of zebrafish macrophages releases M. fortuitum into the extracellular milieu, promoting the production of extracellular cords.…”

Section: Discussionsupporting

confidence: 82%

CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

Johansen

Kremer

2020

Front. Cell. Infect. Microbiol.

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The Mycobacterium fortuitum complex comprises several closely related species, causing pulmonary and extra-pulmonary infections. However, there is very limited knowledge about the disease pathogenesis involved in M. fortuitum infections, particularly due to the lack of suitable animal models. Using the zebrafish model, we show that embryos are susceptible to M. fortuitum infection in a dose-dependent manner. Furthermore, zebrafish embryos form granulomas from as early as 2 days post-infection, recapitulating critical aspects of mycobacterial pathogenesis observed in other pathogenic species. The formation of extracellular cords in infected embryos highlights a previously unknown pathogenic feature of M. fortuitum. The formation of large corded structures occurs also during in vitro growth, suggesting that this is not a host-adapted stress mechanism deployed during infection. Moreover, transient macrophage depletion led to rapid embryo death with increased extracellular cords, indicating that macrophages are essential determinants of M. fortuitum infection control. Importantly, morpholino depletion of the cystic fibrosis transmembrane conductance regulator (cftr) significantly increased embryo death, bacterial burden, bacterial cords and abscesses. There was a noticeable decrease in the number of cftr-deficient infected embryos with granulomas as compared to infected controls, suggesting that loss of CFTR leads to impaired host immune responses and confers hypersusceptiblity to M. fortuitum infection. Overall, these findings highlight the application of the zebrafish embryo to study M. fortuitum and emphasizes previously unexplored aspects of disease pathogenesis of this significant mycobacterial species.

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Section: Discussionsupporting

confidence: 82%

CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

Johansen

Kremer

2020

Front. Cell. Infect. Microbiol.

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“…Activation of ER stress is stimulated by the upregulation of GRP78, which subsequently induces apoptosis signaling mediated by CHOP and caspase-12 through IRE1α-XBP-1, PERK-ATF4, and ATF6-dependent pathways (Zhang and Kaufman, 2008 ). Caspase-12 regulates ER stress-induced apoptosis signaling by activating caspase-9, which consequently activates caspase-3 (Datta et al, 2018 ; Rong et al, 2020 ). CHOP, a transcription factor, activates the expression of anti-apoptotic and pro-apoptotic proteins including those of the Bcl-2 family (Coker-Gurkan et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

Lee

et al. 2021

Front. Cell. Neurosci.

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While it is well-known that pre-stroke exercise conditioning reduces the incidence of stroke and the development of comorbidities, it is unclear whether post-stroke exercise conditioning is also neuroprotective. The present study investigated whether exercise postconditioning (PostE) induced neuroprotection and elucidated the involvement of SIRT1 regulation on the ROS/ER stress pathway. Adult rats were subjected to middle cerebral artery occlusion (MCAO) followed by either: (1) resting; (2) mild exercise postconditioning (MPostE); or (3) intense exercise postconditioning (IPostE). PostE was initiated 24 h after reperfusion and performed on a treadmill. At 1 and 3 days thereafter, we determined infarct volumes, neurological defects, brain edema, apoptotic cell death through measuring pro- (BAX and Caspase-3) and anti-apoptotic (Bcl-2) proteins, and ER stress through the measurement of glucose-regulated protein 78 (GRP78), inositol-requiring 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), Caspase-12, and SIRT1. Proteins were measured by Western blot. ROS production was detected by flow cytometry.Compared to resting rats, both MPostE and IPostE significantly decreased brain infarct volumes and edema, neurological deficits, ROS production, and apoptotic cell death. MPostE further increased Bcl-2 expression and Bcl-2/BAX ratio as well as BAX and Caspase-3 expressions and ROS production (*p < 0.05). Both PostE groups saw decreases in ER stress proteins, while MPostE demonstrated a further reduction in GRP78 (***p < 0.001) and Caspase-12 (*p < 0.05) expressions at 1 day and IRE1α (**p < 0.01) and CHOP (*p < 0.05) expressions at 3 days. Additionally, both PostE groups saw significant increases in SIRT1 expression.In this study, both mild and intense PostE levels induced neuroprotection after stroke through SIRT1 and ROS/ER stress pathway. Additionally, the results may provide a base for our future study regarding the regulation of SIRT1 on the ROS/ER stress pathway in the biochemical processes underlying post-stroke neuroprotection. The results suggest that mild exercise postconditioning might play a similar neuroprotective role as intensive exercise and could be an effective exercise strategy as well.

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“…M. fortuitum was, just recently considered a relevant human pathogen, which might explain the small number of studies conducted. Nevertheless, the ability of M. fortuitum to trigger apoptosis in different hosts by different pathways, namely by caspase activation, and the contribution of cell death in mycobacteria clearance are well documented [48,84,85,86]. Our results suggest that apoptosis mediated by caspase 8 and caspase 3/7 favours M. fortuitum and M. avium intracellular persistence, at least in the early stages of infection.…”

Section: Discussionmentioning

confidence: 55%

Nontuberculous Mycobacteria Persistence in a Cell Model Mimicking Alveolar Macrophages

et al. 2019

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Nontuberculous Mycobacteria (NTM) respiratory infections have been gradually increasing. Here, THP-1 cells were used as a model to evaluate intracellular persistence of three NTM species (reference and clinical strains) in human alveolar macrophages. The contribution of phagosome acidification, nitric oxide (NO) production and cell dead on NTM intracellular fate was assessed. In addition, strains were characterized regarding their repertoire of virulence factors by whole-genome sequencing. NTM experienced different intracellular fates: M. smegmatis and M. fortuitum ATCC 6841 were cleared within 24h. In contrast, M. avium strains (reference/clinical) and M. fortuitum clinical strain were able to replicate. Despite this fact, unexpectedly high percentages of acidified phagosomes were found harbouring rab7, but not CD63. All NTM were able to survive in vitro at acidic pHs, with the exception of M. smegmatis. Our data further suggested a minor role for NO in intracellular persistence and that apoptosis mediated by caspase 8 and 3/7, but not necrosis, is triggered during NTM infection. Insights regarding the bacteria genomic backbone corroborated the virulence potential of M. avium and M. fortuitum. In conclusion, the phenotypic traits detected contrast with those described for M. tuberculosis, pointing out that NTM adopt distinct strategies to manipulate the host immune defense and persist intracellularly.

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Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Cited by 27 publications

References 54 publications

CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

Nontuberculous Mycobacteria Persistence in a Cell Model Mimicking Alveolar Macrophages

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