Transcriptional Adaptation of Drug-tolerant<i>Mycobacterium tuberculosis</i>During Treatment of Human Tuberculosis

Walter, Nicholas D.; Dolganov, Gregory; Garcia, Benjamin J.; Worodria, William; Andama, Alfred; Musisi, Emmanuel; Ayakaka, Irene; Vân, Trần Thị Thanh; Voskuil, Martin I.; Jong, Bouke C. de; Davidson, Rebecca M.; Fingerlin, Tasha E.; Kechris, Katerina; Palmer, Claire; Nahid, Payam; Daley, Charles L.; Geraci, Mark W.; Huang, Laurence; Cattamanchi, Adithya; Strong, Michael; Schoolnik, Gary K.; Davis, J. Lucian

doi:10.1093/infdis/jiv149

Cited by 86 publications

(123 citation statements)

References 48 publications

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“…Specimen collection and laboratory assays followed previously described methods [23]. Briefly, spontaneously expectorated sputum was preserved within 5 minutes in guanidine thiocyanate solution.…”

Section: Enrollment and Specimen Collectionmentioning

confidence: 99%

“…After extraction of total RNA, quality was assessed using a test panel targeting 24 M. tuberculosis transcripts. M. tuberculosis transcriptional profiles were then quantified on good-quality RNA via multiplex quantitative reverse transcription-polymerase chain reaction (qRT-PCR) [23]. Briefly, after first-strand complementary DNA (cDNA) synthesis, cDNA underwent controlled multiplex amplification, using M. tuberculosis-specific flanking primers.…”

Section: Laboratory Analysismentioning

confidence: 99%

“…Understanding the bacterial transcriptional phenotype in clinical samples from patients with tuberculosis is important because transcriptional profiling studies indicate that the physiologic state of M. tuberculosis in human samples differs from the physiologic state of the organism in murine and in vitro models of tuberculosis [23][24][25].…”

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confidence: 99%

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Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

Walter

Jong

Garcia

et al. 2016

The Journal of Infectious Diseases

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Background. It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis in vivo. We evaluated the impact of host immunity by comparing M. tuberculosis and human gene transcription in sputum between human immunodeficiency virus (HIV)-infected and uninfected patients with tuberculosis.Methods. We collected sputum specimens before treatment from Gambians and Ugandans with pulmonary tuberculosis, revealed by positive results of acid-fast bacillus smears. We quantified expression of 2179 M. tuberculosis genes and 234 human immune genes via quantitative reverse transcription-polymerase chain reaction. We summarized genes from key functional categories with significantly increased or decreased expression.Results. A total of 24 of 65 patients with tuberculosis were HIV infected. M. tuberculosis DosR regulon genes were less highly expressed among HIV-infected patients with tuberculosis than among HIV-uninfected patients with tuberculosis (Gambia, P < .0001; Uganda, P = .037). In profiling of human genes from the same sputa, HIV-infected patients had 3.4-fold lower expression of IFNG (P = .005), 4.9-fold higher expression of ARG1 (P = .0006), and 3.4-fold higher expression of IL10 (P = .0002) than in HIVuninfected patients with tuberculosis.Conclusions. M. tuberculosis in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by NO, carbon monoxide, and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages, with consequent decreased NO expression and/or by poor granuloma formation with consequent decreased hypoxic stress.

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Section: Enrollment and Specimen Collectionmentioning

confidence: 99%

Section: Laboratory Analysismentioning

confidence: 99%

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Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

Walter

Jong

Garcia

et al. 2016

The Journal of Infectious Diseases

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“…Gene expression pattern was strikingly different from Mtb cultivated aerobically, and pathways for aerobic respiration and ribosomal function were downregulated but cholesterol utilization was upregulated. In line with findings from different infection and stress models, dosR was the most prominently activated regulon in sputum bacteria [319,320]. The study authors further attempted to model the transcriptomic results using bacteria growing according to the Wayne model, but besides dosR induction, in vitro phenotypes did only poorly recapitulate sputum patterns [319].…”

Section: Mtb Mtb Mtbsupporting

confidence: 56%

“…Recent studies evaluated bacterial transcriptomics of sputum Mtb during antibiotic therapy, and noted the transient induction of INH stress-related genes during the first days of treatment [320,407]. In line with that, TB treatment enriched the lipid droplet-positive population in the sputum of patients [323].…”

Section: Intracellular Mtb Phenotype Intracellular Mtb Phenotype Intrmentioning

confidence: 77%

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

Raffetseder¹

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A Dose‐Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis

Padmapriyadarsini,

Szumowski,

Akbar

et al. 2023

Clin Pharma and Therapeutics

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Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co‐administered with rifampin. We determined in a dose‐escalation clinical trial of persons with pulmonary TB that rifampin‐induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained‐release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0‐12 h) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less‐cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin‐containing treatment regimens.

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Transcriptional Adaptation of Drug-tolerantMycobacterium tuberculosisDuring Treatment of Human Tuberculosis

Cited by 86 publications

References 48 publications

Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

A Dose‐Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis

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