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

Leeuwen, Lisanne M. van; Boot, Maikel; Kuijl, Coenraad; Picavet, Daisy I.; Stempvoort, Gunny van; Pol, Susanne M. A. van der; Vries, Helga E. de; Wel, Nicole N. van der; Kuip, Martijn van der; Furth, A. Marceline van; Sar, Astrid M. van der; Bitter, Wilbert

doi:10.1111/cmi.12858

Cited by 50 publications

(51 citation statements)

References 71 publications

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“…To cross the alveolar barrier directly, the few inhaled M. tb would have to invade AEC, replicate intracellularly, damage the BM, invade EC (and perhaps replicate in them), and then exit to the capillary lumen (Figure 2). This is in line with recent studies on mycobacterial penetration of the blood:brain barrier where Mycobacterium marinum has been demonstrated to transmigrate both via infected-macrophages and by a macrophage-independent mechanism (van Leeuwen et al, 2018). Evidence for M. tb infection of type 2 AEC has been demonstrated in humans (Hernandez-Pando et al, 2000; Eum et al, 2010; Barrios-Payán et al, 2012).…”

Section: Breaching the Alveolar Barrier To Disseminate Systemicallysupporting

confidence: 89%

Mycobacterium tuberculosis Primary Infection and Dissemination: A Critical Role for Alveolar Epithelial Cells

Ryndak

Laal

2019

Front. Cell. Infect. Microbiol.

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Globally, tuberculosis (TB) has reemerged as a major cause of morbidity and mortality, despite the use of the Mycobacterium bovis BCG vaccine and intensive attempts to improve upon BCG or develop new vaccines. Two lacunae in our understanding of the Mycobacterium tuberculosis ( M. tb )-host pathogenesis have mitigated the vaccine efforts; the bacterial-host interaction that enables successful establishment of primary infection and the correlates of protection against TB. The vast majority of vaccine efforts are based on the premise that cell-mediated immunity (CMI) is the predominating mode of protection against TB. However, studies in animal models and in humans demonstrate that post-infection, a period of several weeks precedes the initiation of CMI during which the few inhaled bacteria replicate dramatically and disseminate systemically. The “Trojan Horse” mechanism, wherein M. tb is phagocytosed and transported across the alveolar barrier by infected alveolar macrophages has been long postulated as the sole, primary M. tb :host interaction. In the current review, we present evidence from our studies of transcriptional profiles of M. tb in sputum as it emerges from infectious patients where the bacteria are in a quiescent state, to its adaptations in alveolar epithelial cells where the bacteria transform to a highly replicative and invasive phenotype, to its maintenance of the invasive phenotype in whole blood to the downregulation of invasiveness upon infection of epithelial cells at an extrapulmonary site. Evidence for this alternative mode of infection and dissemination during primary infection is supported by in vivo, in vitro cell-based, and transcriptional studies from multiple investigators in recent years. The proposed alternative mechanism of primary infection and dissemination across the alveolar barrier parallels our understanding of infection and dissemination of other Gram-positive pathogens across their relevant mucosal barriers in that barrier-specific adhesins, toxins, and enzymes synergize to facilitate systemic establishment of infection prior to the emergence of CMI. Further exploration of this M. tb :non-phagocytic cell interaction can provide alternative approaches to vaccine design to prevent infection with M. tb and not only decrease clinical disease but also decrease the overwhelming reservoir of latent TB infection.

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Section: Breaching the Alveolar Barrier To Disseminate Systemicallysupporting

confidence: 89%

Mycobacterium tuberculosis Primary Infection and Dissemination: A Critical Role for Alveolar Epithelial Cells

Ryndak

Laal

2019

Front. Cell. Infect. Microbiol.

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“…5b. The sensitivity of culture and polymerase chain reaction (PCR) of M. tuberculosis from cerebral spinal fluid is very low in patients with TB meningitis [31][32][33] . Given that the blood brain barrier does not allow the components of bacilli to penetrate to the CNS 33 , the frequency of lymphocytes contacting specific antigens in the CNS may be lower than that in the lung, which may explain the increased rate of false negative IGRA results.…”

Section: Discussionmentioning

confidence: 99%

Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis

Yamasue

Komiya

Usagawa

et al. 2020

Sci Rep

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Which factors are related to false negative results of the interferon-γ release assay (iGRA) is unclear. This systematic review described the risk factors associated with false negative IGRA results. Two authors independently identified studies designed to evaluate risk factors for false negative IGRA results from PubMed, the Cochrane Register of Control Trial database, and EMBASE, accessed on October 22, 2018. Meta-analyses were conducted with random-effect models, and heterogeneity was calculated with the I 2 method. Of 1,377 titles and abstracts screened, 47 full texts were selected for review, and we finally included 17 studies in this systematic review. The most commonly studied risk factor (14 studies) was advanced age, followed by low peripheral lymphocyte counts (7 studies), and these factors were associated with false negative results even with different tuberculosis incidences (pooled odds ratio 2.06; 95% CI, 1.68-2.52 in advanced age and 2.68; 95% CI, 2.00-3.61 in low peripheral lymphocyte counts). Advanced age and low peripheral lymphocyte counts may be common risk factors for false negative IGRA results, suggesting that people with these factors need to be carefully followed, even if they have negative iGRA results.

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“…Possibly also other ESX-1 substrates are involved in membrane disruption. However, these other substrates could also be involved in other proposed functions of ESX-1 in pathogenic mycobacterial species, including host cell entry and intercellular spread [11–13].…”

Section: Introductionmentioning

confidence: 99%

Integrated transcriptomic and proteomic analysis of pathogenic mycobacteria and their esx-1 mutants reveal secretion-dependent regulation of ESX-1 substrates and WhiB6 as a transcriptional regulator

et al. 2019

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The mycobacterial type VII secretion system ESX-1 is responsible for the secretion of a number of proteins that play important roles during host infection. The regulation of the expression of secreted proteins is often essential to establish successful infection. Using transcriptome sequencing, we found that the abrogation of ESX-1 function in Mycobacterium marinum leads to a pronounced increase in gene expression levels of the espA operon during the infection of macrophages. In addition, the disruption of ESX-1-mediated protein secretion also leads to a specific down-regulation of the ESX-1 substrates, but not of the structural components of this system, during growth in culture medium. This effect is observed in both M. marinum and M. tuberculosis. We established that down-regulation of ESX-1 substrates is the result of a regulatory process that is influenced by the putative transcriptional regulator whib6, which is located adjacent to the esx-1 locus. In addition, the overexpression of the ESX-1-associated PE35/PPE68 protein pair resulted in a significantly increased secretion of the ESX-1 substrate EsxA, demonstrating a functional link between these proteins. Taken together, these data show that WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates and that ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion.

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

Cited by 50 publications

References 71 publications

Mycobacterium tuberculosis Primary Infection and Dissemination: A Critical Role for Alveolar Epithelial Cells

Mycobacterium tuberculosis Primary Infection and Dissemination: A Critical Role for Alveolar Epithelial Cells

Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis

Integrated transcriptomic and proteomic analysis of pathogenic mycobacteria and their esx-1 mutants reveal secretion-dependent regulation of ESX-1 substrates and WhiB6 as a transcriptional regulator

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