Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages

Gidon, Alexandre; Åsberg, Signe Elisabeth; Louet, Claire; Ryan, Liv; Haug, Markus; Flo, Trude Helen

doi:10.1371/journal.ppat.1006551

Cited by 18 publications

(33 citation statements)

References 77 publications

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“…Thus, we investigated whether the increased kinetic of Mtb targeting to phagolysosomes was due to the differential activation of hLECs by Mtb WT and mutants. We monitored the activation of NF-kB (p65) and IRF-1 after infection of hLECs with Mtb WT, Mtb ΔPDIM and Mtb ΔPDIM∷PDIM by confocal microscopy as previously shown [ 40 , 41 ]. We found that after 24 h of infection, Mtb induced NF-kB activation, as measured by translocation of p65 into the nucleus but this activation was not significantly different between Mtb WT and the mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells

et al. 2018

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BackgroundPhthiocerol dimycocerosates (PDIM), glycolipids found on the outer surface of virulent members of the Mycobacterium tuberculosis (Mtb) complex, are a major contributing factor to the pathogenesis of Mtb. Myelocytic cells, such as macrophages and dendritic cells, are the primary hosts for Mtb after infection and previous studies have shown multiple roles for PDIM in supporting Mtb in these cells. However, Mtb can infect other cell types. We previously showed that Mtb efficiently replicates in human lymphatic endothelial cells (hLECs) and that the hLEC cytosol acts as a reservoir for Mtb in humans. Here, we examined the role of PDIM in Mtb translocation to the cytosol in hLECs.ResultsAnalysis of a Mtb mutant unable to produce PDIM showed less co-localisation of bacteria with the membrane damage marker Galectin-8 (Gal8), indicating that PDIM strongly contribute to phagosomal membrane damage. Lack of this Mtb lipid also leads to a reduction in the proportion of Mtb co-localising with markers of macroautophagic removal of intracellular bacteria (xenophagy) such as ubiquitin, p62 and NDP52. hLEC imaging with transmission electron microscopy shows that Mtb mutants lacking PDIM are much less frequently localised in the cytosol, leading to a lower intracellular burden.ConclusionsPDIM is needed for the disruption of the phagosome membrane in hLEC, helping Mtb avoid the hydrolytic phagolysosomal milieu. It facilitates the translocation of Mtb into the cytosol, and the decreased intracellular burden of Mtb lacking PDIM indicates that the cytosol is the preferred replicative niche for Mtb in these cells. We hypothesise that pharmacological targeting of PDIM synthesis in Mtb would reduce the formation of a lymphatic reservoir of Mtb in humans.

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Section: Resultsmentioning

confidence: 99%

Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells

et al. 2018

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“…Inflammatory responses are central in controlling infection and we have previously shown that negative regulation of inflammatory responses by Keap1 or by depletion of Toll-like receptor (TLR)-signaling facilitates intracellular replication of Mav in human primary macrophages (28–30). We therefore performed a broad systematic screen on the early expression of inflammatory genes to identify changes in immune stimulatory properties that could explain the change in survival.…”

Section: Resultsmentioning

confidence: 99%

“…The levels of IL-1β were highly variable in our experiments. Efficient IL-1β production requires that mycobacteria come in contact with the cytosol and since Mav is not present in the cytosol (30), this could explain the varying results. The ability to activate host defenses by Mav has previously been shown to vary between Mav isolates, and down-regulation of pro-inflammatory cytokines is believed to promote survival of the bacterium (12, 18, 45).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation/evolution and differential host responses resulting from in-patient adaptation ofMycobacterium avium

Kannan

Lai

Haug

et al. 2018

Preprint

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2Mycobacterium avium (Mav) complex (MAC) are characterized as non-tuberculosis 2 3 3 2 form of single nucleotide polymorphisms (SNPs), suggesting that Mav accumulates mutations at 3 3 high rates during persistent infections. Infection of murine macrophages and mice with sequential 3 4 isolates from patients showed a tendency towards increased persistence and down-regulation of 3 5 inflammatory cytokines by host-adapted Mav strains. The study revealed rapid genetic evolution 3 6 of Mav in chronically infected patients accompanied with change in virulence properties of the 3 7 sequential mycobacterial isolates. 3 8 IMPORTANCE 3 9 MAC are a group of opportunistic pathogens, consisting of Mav and M. intracellulare species. 4 0 Mav is found ubiquitously in the environment. In Mav infected individuals, Mav has been known 4 1 to persist for long periods of time, and anti-mycobacterial drugs are unable to effectively clear the 4 2infection. The continued presence of the bacteria, could be attributed to either a single persistent 4 3 strain or reinfection with the same or different strain. We examined sequential isolates collected 4 4 3 over time from Mav infected individuals and observed that most patients carried the same strain 4 5 overtime and were not re infected. We observed high rates of mutation within the serial isolates, 4 6

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“…Efficient IL-1β production requires that mycobacteria come into contact with the cytosol, and since M. avium is not present in the cytosol (32), this could explain the various results. The ability of M.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation ofMycobacterium avium

et al. 2019

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Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. MAC strains show a wide genetic variability, and there is growing evidence suggesting that genetic differences may contribute to a varied immune response that may impact the infection outcome. The current study aimed to characterize the genomic changes within M. avium isolates collected from single patients over time and test the host immune responses to these clinical isolates. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on 40 MAC isolates isolated from 15 patients at the Department of Medical Microbiology at St. Olavs Hospital in Trondheim, Norway. Isolates from patients (patients 4, 9, and 13) for whom more than two isolates were available were selected for further analysis. These isolates exhibited extensive sequence variation in the form of single-nucleotide polymorphisms (SNPs), suggesting that M. avium accumulates mutations at higher rates during persistent infections than other mycobacteria. Infection of murine macrophages and mice with sequential isolates from patients showed a tendency toward increased persistence and the downregulation of inflammatory cytokines by host-adapted M. avium strains. The study revealed the rapid genetic evolution of M. avium in chronically infected patients, accompanied by changes in the virulence properties of the sequential mycobacterial isolates.

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Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages

Cited by 18 publications

References 77 publications

Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells

Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells

Genetic variation/evolution and differential host responses resulting from in-patient adaptation ofMycobacterium avium

Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation ofMycobacterium avium

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