Dichotomous Role of the Macrophage in Early Mycobacterium marinum Infection of the Zebrafish

Clay, Hilary; Davis, J. Muse; Beery, Dana; Huttenlocher, Anna; Lyons, Susan E.; Ramakrishnan, Lalita

doi:10.1016/j.chom.2007.06.004

Cited by 217 publications

(287 citation statements)

References 62 publications

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“…To verify that TgBAC(tnfa:GFP) fish are responsive to inflammatory stimuli in vivo, stable TgBAC(tnfa:GFP) fish were infected with Mycobacterium marinum, a close genetic relative of Mycobacterium tuberculosis and a potent inflammatory stimulus in zebrafish (23,24). Although sham-infected fish did not up-regulate TgBAC(tnfa:GFP) expression, fish infected with fluorescently labeled M. marinum showed a robust up-regulation of tnfa:GFP in granulomas surrounding the bacteria, with kinetics similar to what has been observed via qPCR and in situ hybridization (23,25) (Fig. S3).…”

Section: Resultsmentioning

confidence: 91%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

170

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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Section: Resultsmentioning

confidence: 91%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

170

168

View full text Add to dashboard Cite

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“…by injecting antisense morpholinos against the myeloid transcription factor gene pu.1 (37). Morphant embryos infected with either the M. abscessus R or S variant displayed heavy bacterial burdens (Fig.…”

Section: Abscessus S and R Variants Are Rapidly And Equally Phagocmentioning

confidence: 99%

“…A mix of splice-blocking 5′-GGTCTTTCTCCTTAC-CATGCTCTCC-3′ and ATG 5′-CCTCCATTCTGTACGGATGCAGCAT-3′ morpholinos against pu.1 gene were purchased from Gene Tools and combined as described (37). The morpholino mix was prepared in morpholino buffer containing 10% (vol/vol) phenol red, and 3 nL was injected into one-cell-stage mpeg1:mCherry and mpx:egfp ZF.…”

Section: Microinjection Of Morpholinosmentioning

confidence: 99%

Mycobacterium abscessus cording prevents phagocytosis and promotes abscess formation

Bernut

Herrmann

Kissa

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

302

493

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Mycobacterium abscessus is a rapidly growing Mycobacterium causing a wide spectrum of clinical syndromes. It now is recognized as a pulmonary pathogen to which cystic fibrosis patients have a particular susceptibility. The M. abscessus rough (R) variant, devoid of cell-surface glycopeptidolipids (GPLs), causes more severe clinical disease than the smooth (S) variant, but the underlying mechanisms of R-variant virulence remain obscure. Exploiting the optical transparency of zebrafish embryos, we observed that the increased virulence of the M. abscessus R variant compared with the S variant correlated with the loss of GPL production. The virulence of the R variant involved the massive production of serpentine cords, absent during S-variant infection, and the cords initiated abscess formation leading to rapid larval death. Cording occurred within the vasculature and was highly pronounced in the central nervous system (CNS). It appears that M. abscessus is transported to the CNS within macrophages. The release of M. abscessus from apoptotic macrophages initiated the formation of cords that grew too large to be phagocytized by macrophages or neutrophils. This study is a description of the crucial role of cording in the in vivo physiopathology of M. abscessus infection and emphasizes cording as a mechanism of immune evasion.morphotype | pathogenesis | granuloma | innate immunity T he rapidly growing mycobacterium (RGM) Mycobacterium abscessus (M. abscessus) is an emerging pathogen that infects a wide spectrum of tissues in humans, including lungs, skin, and soft tissues (1, 2). M. abscessus lung disease is highly prevalent in patients with cystic fibrosis (CF) and is becoming a major issue for most CF centers worldwide (3-6). Although M. abscessus is an RGM, it can persist and cause lung disease with caseous lesions (7).M. abscessus exists as two variants: rough (R) and smooth (S). Ex vivo and in vivo studies have described the hypervirulence phenotype of the R versus the S morphotype (8, 9), and epidemiological studies have confirmed the persistence and acute respiratory syndromes caused by the R morphotype (4, 10, 11). The major difference between the R and S variants is the loss of a surface-associated glycopeptidolipid (GPL) (12). Analysis of the pathogenicity of M. abscessus has been hampered by the lack of genetic tools and the restricted panel of cellular/animal models. However, new genetic tools, including conditional gene expression, recently have been applied to both the S and R morphotypes (13, 14), but developing new animal models amenable to the manipulation of the host response is still challenging. The M. abscessus genome harbors a mercury-resistance plasmid sharing 99% identity with an episome from the slowgrowing fish pathogen Mycobacterium marinum, indicating that these species have exchanged this plasmid in a shared ecosystem (15). M. abscessus has been described in wild and captive fish species (16,17), and hand infections caused by M. abscessus have been reported in healthy fish handlers (18), sug...

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“…1) (Wells et al 1948;Bates et al 1965;Dannenberg 1993;Wolf et al 2007). Experiments in zebrafish larvae modeling these early interactions show that macrophages recruited to the site of infection engulf the mycobacteria and transport them into deeper tissues (Clay et al 2007). The observation that macrophage depletion prevents tissue dissemination underscores the role of macrophages in transporting the bacteria from their site of pathogen entry into distal tissues, a step that is required for development and transmission of TB.…”

Section: Leading Up To the Granuloma Poor Microbicidal Macrophages Trmentioning

confidence: 99%