Mycobacterium tuberculosis cording in alveolar macrophages of patients with pulmonary tuberculosis is likely associated with increased mycobacterial virulence

Ufimtseva, Elena; Eremeeva, Natalya; Petrunina, Ekaterina; Umpeleva, Tatiana; Bayborodin, Sergey I.; Vakhrusheva, Diana; Skornyakov, Sergey

doi:10.1016/j.tube.2018.07.001

Cited by 21 publications

(27 citation statements)

References 43 publications

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“…Aggregated Mtb infection led to neutrophil accumulation in a mouse model [11]. Death of Mtb infected neutrophils may also enhance Mtb growth, which we have observed to be accelerated in dead infected cells [15] and may make aggregated Mtb a more virulent form of infection [12, 11, 46, 17, 10]. In support of this, we observed that Mtb aggregates occurred at a substantial frequency around a TB cavitary lesion.…”

Section: Discussionsupporting

confidence: 70%

“…The host-pathogen interactions that tip the balance to active disease are not clearly defined. Aggregation has been proposed to be associated with pathogenicity [9, 10] and increase Mtb virulence in mice and ex vivo [11, 12, 13]. Mtb aggregates have been observed in human lung tissue [7], though the fraction of bacilli in this state is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Aggregated Mycobacterium tuberculosis enhances the inflammatory response

Sigal

Rodel

Ferreira

et al. 2021

Preprint

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Mycobacterium tuberculosis (Mtb) readily aggregates in culture and Mtb aggregates in the lung were observed in experimental Mtb infection. However, the physiological consequences of Mtb aggregation are incompletely understood. Here we examined the human macrophage transcriptional response to aggregated Mtb relative to infection with non-aggregated single or multiple bacilli per host cell. Infection with aggregated Mtb led to an early upregulation of pro-inflammatory associated genes and enhanced TNFα signaling via the NFκB pathway. Both these pathways were significantly upregulated relative to infection with single bacilli, and TNFα signaling was also significantly elevated relative to infection with multiple non-aggregated Mtb. Secretion of TNFα and downstream cytokines were also enhanced. On a longer timescale, aggregate infection led to overall increased acidification per macrophage and a high proportion of death in these cells after aggregate phagocytosis. Host cell death did not occur when Mtb aggregates were heat killed despite such clumps being readily picked up. To validate that Mtb aggregates do occur in the human lung, we document Mtb aggregates surrounding a cavity in a human TB lesion. Aggregates may therefore be present in some lesions and elicit a stronger inflammatory response resulting in recruitment of additional phagocytes and their subsequent death, potentially leading to necrosis and transmission.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Aggregated Mycobacterium tuberculosis enhances the inflammatory response

Sigal

Rodel

Ferreira

et al. 2021

Preprint

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“…Recently, the cording phenotype has been shown to cause extensive immunopathological changes associated with active TB in C3HeB/FeJ mice (6). Mtb cords were also identified inside human alveolar macrophages obtained from patients with active TB (7) and lymphatic endothelial cells isolated from patients with extrapulmonary TB (8).…”

Section: Resultsmentioning

confidence: 99%

“…IC50and MIC values for RIF and INH and the other antibiotics tested.Heterogeneity of mycobacterial phenotypes in infected tissues and changing microenvironmentduring the course of TB poses a challenge for successful treatment that eliminates all forms of the pathogen. As we and others have previously demonstrated, the cording phenotype has possible bearings on TB severity, as it contributes to the pathophysiology(7,8) and causes MET formation in infected macrophages(5). This prompted us to compare the effect of antibiotics on cording and planktonic mycobacteria.Bacterial suspension is routinely homogenized as prerequisite for assessment of its concentration with help of OD measurements(19,20).…”

mentioning

confidence: 98%

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

Kalsum

Andersson

Das

et al. 2021

Preprint

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Background Assays enabling efficient high throughput drug screening are necessary for the discovery of new anti-mycobacterial drugs. The purpose of our work was to develop and validate an assay based on live-cell imaging which can monitor growth of two distinct phenotypes of Mycobacterium tuberculosis and to test their susceptibility to commonly used TB drugs. Results Both planktonic and cording phenotypes were successfully monitored as fluorescent objects using the live-cell imaging system Incucyte S3, allowing collection of data describing distinct characteristics of aggregate size and growth. The quantification of changes in total area of aggregates was used to define IC50 and MIC values of selected TB drugs which revealed that the cording phenotype grew more rapidly and displayed a higher susceptibility to rifampicin. A checkerboard approach, testing pair-wise combinations of sub-inhibitory concentrations of drugs, revealed rifampicin, linezolid and pretomanid as superior in inhibiting growth of cording phenotype. Conclusion Our results emphasize the efficiency of using automated live-cell imaging and its potential in high-through put whole-cell screening to evaluate existing and search for novel antimycobacterial drugs.

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“…Heterogeneity of mycobacterial phenotypes in infected tissues and changing microenvironment during the course of TB poses a challenge for successful treatment that eliminates all forms of the pathogen. As we and others have previously demonstrated, the cording phenotype has possible bearings on TB severity, as it contributes to the pathophysiology [ 8 , 9 ] and causes MET formation in infected macrophages [ 6 ]. This prompted us to compare the effect of antibiotics on cording and planktonic mycobacteria.…”

Section: Discussionmentioning

confidence: 99%

A high-throughput screening assay based on automated microscopy for monitoring antibiotic susceptibility of Mycobacterium tuberculosis phenotypes

et al. 2021

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Background Efficient high-throughput drug screening assays are necessary to enable the discovery of new anti-mycobacterial drugs. The purpose of our work was to develop and validate an assay based on live-cell imaging which can monitor the growth of two distinct phenotypes of Mycobacterium tuberculosis and to test their susceptibility to commonly used TB drugs. Results Both planktonic and cording phenotypes were successfully monitored as fluorescent objects using the live-cell imaging system IncuCyte S3, allowing collection of data describing distinct characteristics of aggregate size and growth. The quantification of changes in total area of aggregates was used to define IC50 and MIC values of selected TB drugs which revealed that the cording phenotype grew more rapidly and displayed a higher susceptibility to rifampicin. In checkerboard approach, testing pair-wise combinations of sub-inhibitory concentrations of drugs, rifampicin, linezolid and pretomanid demonstrated superior growth inhibition of cording phenotype. Conclusions Our results emphasize the efficiency of using automated live-cell imaging and its potential in high-throughput whole-cell screening to evaluate existing and search for novel antimycobacterial drugs.

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Mycobacterium tuberculosis cording in alveolar macrophages of patients with pulmonary tuberculosis is likely associated with increased mycobacterial virulence

Cited by 21 publications

References 43 publications

Aggregated Mycobacterium tuberculosis enhances the inflammatory response

Aggregated Mycobacterium tuberculosis enhances the inflammatory response

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

A high-throughput screening assay based on automated microscopy for monitoring antibiotic susceptibility of Mycobacterium tuberculosis phenotypes

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