Visualization of Macrophage Lytic Cell Death During Mycobacterial Infection in Zebrafish Embryos via Intravital Microscopy

Niu, Liangfei; Zhang, Kaile; Kang, Miaomiao; Liang, Rui; Zhang, Xiaonan; Yan, Bo

doi:10.3791/60698

Cited by 8 publications

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“…The treatment failure might be related to low drug concentration levels in plasma [ 28 ], decreases in the bioavailability of rifampicin [ 29 ], unsteady state of drug exposure [ 30 ], Substandard and falsified drugs [ 31 ], or the drug resistance occurred during the treatment since patients with evidence of drug-resistance were excluded. And granulomas lesions aroused by macrophage lytic cell death might be involved in this process [ 32 ]. The question is now, how to treat the patients when they develop pleural-based masses?…”

Section: Discussionmentioning

confidence: 99%

Paradoxical development of pleural-based masses in patients with pleural tuberculosis during treatment: a clinical observational study in China

et al. 2022

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Background To explored the clinical, pathological, and bacteriological characteristics of pleural-based masses occurred during anti-tuberculosis (TB) treatment in patients with pleural TB. Methods Patients referred with newly diagnosed pleural TB were prospectively enrolled into the study. Patients were followed up throughout the treatment, and clinical data were recorded. Percutaneous biopsy and surgical tissues from pleural-based masses were examined histologically and samples sent for PCR. Cytokines in the pleural effusions and clinical factors were collected and compared between different patients. Results A total of 122 patients with pleural TB were enrolled, and 34.4% (42/122) displayed newly observed pleural-based mass during the treatment. Twelve cases underwent surgical resection at the 12 ± 0.5 months during the treatment course. Based on the surgical observation, 58.3% (7 /12) were located in pleura, 41.7% (5/12) were located in the lung parenchyma. Pathological observations showed that the pleural-based masses were typed as granulomatous inflammation, fibrous hyperplasia and necrosis. Mycobacterium tuberculosis PCR was positive in 57.1% of the cases (24/42). Any first-line anti-TB drug resistance gene mutations were positive in only 9.5% (4/42). Aside from 12 cases who underwent the surgical operation, 86.7% of the patients (26/30) still had a pleural-based mass at the end of 12 months treatment course. Patients with a pleural-based mass were younger, had a thicker pleural, a higher proportion of pleural adhesive, loculated pleural effusion and residual pleural effusion, and a higher level of LDH, ADA and lower glucose in pleural effusion than those without a pleural-based mass occurrence during the treatment (all Pcorr < 0.05). Conclusions Pleural-based masses were observed in about one-third of patients with pleural TB. The masses were in the lung or pleura and were divided into three pathological types.

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Section: Discussionmentioning

confidence: 99%

Paradoxical development of pleural-based masses in patients with pleural tuberculosis during treatment: a clinical observational study in China

et al. 2022

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“…This might be the result of the increased il-1β production during the early infection, as il-1β has been shown to be a potent stimulus for neutrophil recruitment ( 48 , 58 ). Another possibility is that the elevated tnf-α expression leads to macrophage lysis, and the intracellular material released by lytic cell death functions as a neutrophil attractant ( 39 , 47 ). This is consistent with a recent study showing that macrophage pyroptosis is beneficial for host control of mycobacterial infection ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

“…Zebrafish embryo infections were performed by microinjection of M. marinum via the duct of Cuvier unless otherwise indicated ( 46 ). For live imaging and Sudan Black (SB) staining, infections were by subcutaneous injection ( 47 ). The infecting dose was 250 CFU, if not otherwise specified, but 400 CFU were used for experiments designed for analysis by FACS.…”

Section: Methodsmentioning

confidence: 99%

Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish

et al. 2022

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The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.

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“…M. marinum M strain (ATCC BAA-535, labeled with Wasabi fluorescence) was grown in the 7H9 liquid medium at 32°C as previously described ( Niu et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Tibetan medicine salidroside improves host anti-mycobacterial response by boosting inflammatory cytokine production in zebrafish

Fan

Sun

et al. 2022

Front. Pharmacol.

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The treatment for tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), has a prolonged cycle which can last up to a year. This is partially due to the lack of effective therapies. The development of novel anti-TB drugs from the perspective of host immune regulation can provide an important supplement for conventional treatment strategies. Salidroside (SAL), a bioactive component from the Tibetan medicine Rhodiola rosea, has been used in the treatment of TB, although its mechanism remains unclear. Here, the bacteriostatic effect of SAL in vivo was first demonstrated using a zebrafish–M. marinum infection model. To further investigate the underlying mechanism, we then examined the impact of SAL on immune cell recruitment during wound and infection. Increased macrophage and neutrophil infiltrations were found both in the vicinity of the wound and infection sites after SAL treatment compared with control, which might be due to the elevated chemokine expression levels after SAL treatment. SAL treatment alone was also demonstrated to improve the survival of infected zebrafish larvae, an effect that was amplified when combining SAL treatment with isoniazid or rifampicin. Interestingly, the reduced bacterial burden and improved survival rate under SAL treatment were compromised in tnfα-deficient embryos which suggests a requirement of Tnfα signaling on the anti-mycobacterial effects of SAL. In summary, this study provides not only the cellular and molecular mechanisms for the host anti-mycobacterial effects of the Tibetan medicine SAL but also proof of concept that combined application of SAL with traditional first-line anti-TB drugs could be a novel strategy to improve treatment efficacy.

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Visualization of Macrophage Lytic Cell Death During Mycobacterial Infection in Zebrafish Embryos via Intravital Microscopy

Cited by 8 publications

References 0 publications

Paradoxical development of pleural-based masses in patients with pleural tuberculosis during treatment: a clinical observational study in China

Paradoxical development of pleural-based masses in patients with pleural tuberculosis during treatment: a clinical observational study in China

Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish

Tibetan medicine salidroside improves host anti-mycobacterial response by boosting inflammatory cytokine production in zebrafish

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