M. tuberculosis and M. leprae Translocate from the Phagolysosome to the Cytosol in Myeloid Cells

Wel, Nicole N. van der; Hava, David L.; Houben, Diane; Fluitsma, Donna; Zon, Maaike van; Pierson, Jason; Brenner, Michael B.; Peters, Peter J.

doi:10.1016/j.cell.2007.05.059

Cited by 868 publications

(875 citation statements)

References 52 publications

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“…Bacterial levels at 24‐hr postinfection (hpi) were analysed with FACS and compared with uptake of these bacteria by RAW macrophages. RAW macrophages phagocytosed both strains with similar efficiency, both at 2 and 24 hpi (Figure 7a), confirming previous reports that the level of phagocytosis of M. marinum WT and our esx‐1 mutant are similar (Houben et al, 2012; Simeone et al, 2012; van der Wel et al, 2007). …”

Section: Resultssupporting

confidence: 89%

“…ESX‐1 secretion mutants are severely attenuated (Davis & Ramakrishnan, 2009; Stoop et al, 2011; Volkman et al, 2004), but most importantly for our purposes, these mutants are unable to complete the macrophage infection cycle and are therefore predominantly located inside phagocytic cells (Houben et al, 2012; Simeone et al, 2012; van der Wel et al, 2007). …”

Section: Resultsmentioning

confidence: 99%

“…Our data suggest that ESX‐1 substrates mediate an active process in which M. marinum is able to invade endothelial cells. This attributes a novel function to ESX‐1 secretion, in addition to phagosomal escape (Abdallah et al, 2011; Houben et al, 2012; Simeone et al, 2012; van der Wel et al, 2007). Furthermore, the damaging effect of mycobacteria on endothelial cells might be part of the explanation for the extensive vasculopathy, including stroke and vasculitis, found in clinical TBM presentation and autopsy material (Donald & Van Toorn, 2016; van der Flier et al, 2004; Zaharie et al, unpublished).…”

Section: Discussionmentioning

confidence: 99%

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Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Leeuwen

Boot

Kuijl

et al. 2018

Cellular Microbiology

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Central nervous system (CNS) infection by Mycobacterium tuberculosis is one of the most devastating complications of tuberculosis, in particular in early childhood. In order to induce CNS infection, M. tuberculosis needs to cross specialised barriers protecting the brain. How M. tuberculosis crosses the blood–brain barrier (BBB) and enters the CNS is not well understood. Here, we use transparent zebrafish larvae and the closely related pathogen Mycobacterium marinum to answer this question. We show that in the early stages of development, mycobacteria rapidly infect brain tissue, either as free mycobacteria or within circulating macrophages. After the formation of a functionally intact BBB, the infiltration of brain tissue by infected macrophages is delayed, but not blocked, suggesting that crossing the BBB via phagocytic cells is one of the mechanisms used by mycobacteria to invade the CNS. Interestingly, depletion of phagocytic cells did not prevent M. marinum from infecting the brain tissue, indicating that free mycobacteria can independently cause brain infection. Detailed analysis showed that mycobacteria are able to cause vasculitis by extracellular outgrowth in the smaller blood vessels and by infecting endothelial cells. Importantly, we could show that this second mechanism is an active process that depends on an intact ESX‐1 secretion system, which extends the role of ESX‐1 secretion beyond the macrophage infection cycle.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Leeuwen

Boot

Kuijl

et al. 2018

Cellular Microbiology

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“…The recombinant BCG::RD1-strain expressing the ESAT-6 secretion system showed similar TB10.4 epitope recognition patterns as virulent M.tb, both recognizing the MHC-I restricted epitopes in P1 and P2 and the MHC-II restricted epitope in P8 (data not shown), corresponding to earlier described epitopes [24,26,27]. As it has been suggested that the RD1 region enables M.tb to escape the phagosome [28], it could be speculated that altered intracellular trafficking of BCG might lead to a different epitope pattern and/ or to new protective epitopes.The comparison of the CD4 1 T-cell responses induced in our study revealed that BCG and M.tb both induced T cells specific for the known epitope residing in TB10.4-P8 [27], whereas P3 and P7 were the main epitopes recognized following TB10.4 vaccination, in agreement with an earlier study ( Fig. 1 and 2 [15]).…”

supporting

confidence: 65%

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

et al. 2010

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Most novel vaccines against infectious diseases are based on recombinant Ag; however, only few studies have compared Ag-specific immune responses induced by natural infection with that induced by the same Ag in a recombinant form. Here, we studied the epitope recognition pattern of the tuberculosis vaccine Ag, TB10.4, in a recombinant form, or when expressed by the pathogen Mycobacterium tuberculosis (M.tb), or by the current anti-tuberculosis vaccine, Mycobacterium bovis BCG. We showed that BCG and M.tb induced a similar CD4 1 T-cell specific TB10.4 epitope-pattern, which differed completely from that induced by recombinant TB10.4. This difference was not due to post-translational modifications of TB10.4 or because TB10.4 is secreted from BCG and M.tb as a complex with Rv0287. In addition, BCG and TB10.4/CAF01 were both taken up by DC and macrophages in vivo, and in vitro uptake experiments revealed that both TB10.4 and BCG were transported to Lamp 1 -compartments. BCG and TB10.4 however, were directed to different types of Lamp 1 -compartments in the same APC, which may lead to different epitope recognition patterns. In conclusion, we show that different vectors can induce completely different recognition of the same protein.Key words: Epitopes . Intracellular localization . Subdominant . T cells . Vaccine uptake IntroductionThe size, shape and nature of a synthetic recombinant vaccine and its target pathogen differ significantly. For instance, bacteria are typically in the range of 0.5-10 mm in diameter, which exceed the size of most viruses by 10 to 100-fold, and protein based adjuvanted vaccines are even smaller. In addition, compared with vaccines based on recombinant proteins and an adjuvant, pathogens are often taken up by different mechanisms by the cells of the immune system [1]. The different uptake mechanisms could lead to different intracellular processing of Ag, giving rise to different epitopes [1]. Furthermore, live pathogens express a wide range of specific lipids 1342and proteins that bind a variety of pattern-recognition receptors on phagocytes and induce signaling through these receptors, whereas recent evidence suggests subunit vaccines more specifically tend to target DC through activation of toll-like receptors [2]. These differences are likely to lead to different responses with regard to the priming of the early immune response [3]. For instance, the main host cell of the intracellular pathogen Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis in humans, is thought to be macrophages [4]; however, although mycobacteria are mainly taken up by macrophages, mycobacteria can infect a wide range of cells including neutrophils, epithelial cells and other cell types [5,6]. On the other hand, viral vaccine vectors have been shown to be ingested largely by immature DC [1], and soluble Ag formulated in cationic adjuvants such as CAF01 or IC31 are also believed to target DC [7,8]. Different types of APC have different mechanisms of Ag uptake, different pH levels in lysosomal co...

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“…In vitro studies using electron microscopy (EM) and a fluorescence resonance energy transfer‐based method showed that Mtb also localizes in the cytosol in THP‐1 macrophages, primary human macrophages and primary human DCs (van der Wel et al ., 2007; Houben et al ., 2012; Simeone et al ., 2012). The ESX‐1 type VII secretion system (T7SS) that is lacking from most of the non‐pathogenic mycobacterial strains (Abdallah et al ., 2007) is required for Mtb localization in the cytosol.…”

Section: Cell Autonomous Defence Mechanisms In Tbmentioning

confidence: 99%

The innate immune response in human tuberculosis

2015

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Summary M ycobacterium tuberculosis (Mtb) infection can be cleared by the innate immune system before the initiation of an adaptive immune response. This innate protection requires a variety of robust cell autonomous responses from many different host immune cell types. However, Mtb has evolved strategies to circumvent some of these defences. In this mini‐review, we discuss these host–pathogen interactions with a focus on studies performed in human cells and/or supported by human genetics studies (such as genome‐wide association studies).

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M. tuberculosis and M. leprae Translocate from the Phagolysosome to the Cytosol in Myeloid Cells

Cited by 868 publications

References 52 publications

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

The innate immune response in human tuberculosis

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