Mycobacterial Lipid Bodies and the Chemosensitivity and Transmission of Tuberculosis

Garton, Natalie J.; Barer, Michael R.

doi:10.1007/978-3-030-15147-8_6

Cited by 3 publications

(4 citation statements)

References 74 publications

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“…The physiological state of aerosolized organisms remains uncertain owing to the previous unavailability of tools to investigate this stage of the TB disease cycle. Although DMN-trehalose positivity alone implies metabolic activity (bacilli must be viable to incorporate the trehalose analog into the mycomembrane), it is not known if these organisms are replicatively active, nor if aerosolized bacilli contain defining alterations in cell envelope [26] or other macromolecular compositions and/or inclusions [27]. We determined the sensitivity of DMN-trehalose labelling to metabolic state as a function of log versus stationary phase growth, recording significant differences that could be used to distinguish these states.…”

Section: Discussionmentioning

confidence: 99%

Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols

et al. 2021

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Interrupting transmission is an attractive anti-tuberculosis (TB) strategy but it remains underexplored owing to our poor understanding of the events surrounding transfer of Mycobacterium tuberculosis (Mtb) between hosts. Determining when live, infectious Mtb bacilli are released and by whom has proven especially challenging. Consequently, transmission chains are inferred only retrospectively, when new cases are diagnosed. This process, which relies on molecular analyses of Mtb isolates for epidemiological fingerprinting, is confounded by the prolonged infectious period of TB and the potential for transmission from transient exposures. We developed a Respiratory Aerosol Sampling Chamber (RASC) equipped with high-efficiency filtration and sampling technologies for liquid-capture of all particulate matter (including Mtb) released during respiration and non-induced cough. Combining the mycobacterial cell wall probe, DMN-trehalose, with fluorescence microscopy of RASC-captured bioaerosols, we detected and quantified putative live Mtb bacilli in bioaerosol samples arrayed in nanowell devices. The RASC enabled non-invasive capture and isolation of viable Mtb from bioaerosol within 24 hours of collection. A median 14 live Mtb bacilli (range 0–36) were isolated in single-cell format from 90% of confirmed TB patients following 60 minutes bioaerosol sampling. This represented a significant increase over previous estimates of transmission potential, implying that many more organisms might be released daily than commonly assumed. Moreover, variations in DMN-trehalose incorporation profiles suggested metabolic heterogeneity in aerosolized Mtb. Finally, preliminary analyses indicated the capacity for serial image capture and analysis of nanowell-arrayed bacilli for periods extending into weeks. These observations support the application of this technology to longstanding questions in TB transmission including the propensity for asymptomatic transmission, the impact of TB treatment on Mtb bioaerosol release, and the physiological state of aerosolized bacilli.

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Section: Discussionmentioning

confidence: 99%

Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols

et al. 2021

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“…More generally, lipid-rich cells surviving treatment are thought to play a central role in patient relapse 21 . Further, in vitro and clinical studies exploring the role of lipid bodies in defining the outcome of infection and their use as biomarker for treatment outcome are still required 18 .…”

Section: Discussionmentioning

confidence: 99%

“…In recent clinical trials, relapse was identified as a major barrier to shorten tuberculosis (TB) antibiotic treatment regimens [15][16][17] . There is increasing evidence supporting the clinical significance of the presence of lipid bodies in M. tuberculosis cells 18 . A higher risk of poor TB treatment outcome correlates with a higher proportion of mycobacteria with lipid inclusions in patients sputum after 3 and 4 weeks of treatment 19 .…”

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confidence: 99%

Real-time monitoring of live mycobacteria with a microfluidic acoustic-Raman platform

et al. 2020

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Tuberculosis (TB) remains a leading cause of death worldwide. Lipid rich, phenotypically antibiotic tolerant, bacteria are more resistant to antibiotics and may be responsible for relapse and the need for long-term TB treatment. We present a microfluidic system that acoustically traps live mycobacteria, M. smegmatis, a model organism for M. tuberculosis. We then perform optical analysis in the form of wavelength modulated Raman spectroscopy (WMRS) on the trapped M. smegmatis for up to eight hours, and also in the presence of isoniazid (INH). The Raman fingerprints of M. smegmatis exposed to INH change substantially in comparison to the unstressed condition. Our work provides a real-time assessment of the impact of INH on the increase of lipids in these mycobacteria, which could render the cells more tolerant to antibiotics. This microfluidic platform may be used to study any microorganism and to dynamically monitor its response to different conditions and stimuli.

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“…The clinical relevance of LD-positive Mtb bacilli in sputum was first elucidated by Garton and colleagues [ 29 , 88 ]. These studies concluded that the proportion of LD-positive Mtb in sputum lies between 3 and 86%, with 2–8 LDs/bacilli [ 29 ].…”

Section: Clinical Relevance Of M Tuberculosis Lipid Dropletsmentioning

confidence: 99%

Lipid droplets and the transcriptome of Mycobacterium tuberculosis from direct sputa: a literature review

et al. 2021

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Mycobacterium tuberculosis (Mtb), the main etiology of tuberculosis (TB), is predominantly an intracellular pathogen that has caused infection, disease and death in humans for centuries. Lipid droplets (LDs) are dynamic intracellular organelles that are found across the evolutionary tree of life. This review is an evaluation of the current state of knowledge regarding Mtb-LD formation and associated Mtb transcriptome directly from sputa.Based on the LD content, Mtb in sputum may be classified into three groups: LD positive, LD negative and LD borderline. However, the clinical and evolutionary importance of each state is not well elaborated. Mounting evidence supports the view that the presence of LD positive Mtb bacilli in sputum is a biomarker of slow growth, low energy state, towards lipid degradation, and drug tolerance. In Mtb, LD may serve as a source of chemical energy, scavenger of toxic compounds, prevent destruction of Mtb through autophagy, delay trafficking of lysosomes towards the phagosome, and contribute to Mtb persistence. It is suggest that LD is a key player in the induction of a spectrum of phenotypic and metabolic states of Mtb in the macrophage, granuloma and extracellular sputum microenvironment. Tuberculosis patients with high proportion of LD positive Mtb in pretreatment sputum was associated with higher rate of poor treatment outcome, indicating that LD may have a clinical application in predicting treatment outcome.The propensity for LD formation among Mtb lineages is largely unknown. The role of LD on Mtb transmission and disease phenotype (pulmonary TB vs extra-pulmonary TB) is not well understood. Thus, further studies are needed to understand the relationships between LD positivity and Mtb lineage, Mtb transmission and clinical types.

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Mycobacterial Lipid Bodies and the Chemosensitivity and Transmission of Tuberculosis

Cited by 3 publications

References 74 publications

Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols

Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols

Real-time monitoring of live mycobacteria with a microfluidic acoustic-Raman platform

Lipid droplets and the transcriptome of Mycobacterium tuberculosis from direct sputa: a literature review

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