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Mycobacterium tuberculosis HN878 transcriptomes from replicating broth culture, THP1 macrophage-like cells, caseum surrogate, and rabbit caseum

ABSTRACT: Among the many influences affecting patient outcomes, the heterogeneity of Mtb populations in remote lesion compartments and the nature of pathogen physiology in these stressful environments are increasingly appreciated as factors that limit the efficacy of current therapies. The transcriptional state of Mtb during infection has been difficult to study and represents a potentially game-changing area for intervention. Limited studies in humans and animals have suggested that subpopulations of Mtb persist in the caseum (soft necrotic debris) that accumulates in the center of necrotic TB granulomas. Stress factors in the caseous foci include hypoxia, iron deprivation, and nutrient limitation. To persist in this environment, it is likely that this population elicits sweeping, transcriptionally coordinated molecular changes that are reflected in their gene expression profiles. Determining the basis of Mtb’s ability to persist in this environment is a critical hurdle in addressing whether intracaseum Mtb are the rate-limiting step for successfully curing TB infection and designing interventions specific to this subpopulation. To address this population, we are adapting the developing GenomeCaptureSeq technology to isolate TB transcripts, determine the transcriptional profile of Mtb in caseum and characterize caseum-specific molecular programs that are utilized by Mtb in this environment to generate targets for intervention. This process involves fragmenting Mtb genomic DNA, linking to beads and then fishing Mtb transcripts from caseous material. Our approach has been applied to caseum samples from Mtb-infected rabbits and we have successfully sequenced TB-specific transcripts from multiple infected lesions. We aim to define a caseum-specific transcriptional signature that will help direct future studies of this subpopulation of interest.

ORGANISM(S): Mycobacterium tuberculosis

PROVIDER: GSE273037 | GEO | 2025/07/01

REPOSITORIES: GEO

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Project description:The lengthy and complicated multidrug therapy currently available to treat active tuberculosis (TB) infection has contributed to medical non-adherence and the emerging problems of multidrug-resistant (MDR)- and extensively drug-resistant (XDR)-TB, which are particularly deadly in the setting of HIV co-infection. The prolonged therapy required to eradicate TB infection is believed to reflect the ability of Mycobacterium tuberculosis (Mtb) to persist within host necrotic granulomas in a non-replicating state characterized by antibiotic tolerance to bactericidal drugs, which predominantly target actively dividing tubercle bacilli. The stringent response enzyme, RelMtb, is essential for Mtb survival under physiologically relevant stress conditions in vitro and in the lungs of mice and guinea pigs. A library of over 2 million compounds was screened in RelMtb-inhibition assays and whole-cell screens under conditions in which RelMtb is essential. A total of 178 RelMtb inhibitor candidates, representing 18 unique scaffolds, were identified and 39 compounds were tested against nutrient-starved wild-type Mtb. The antibiotic susceptibility of a relMtb deletion mutant (Δrel) was studied during nutrient starvation and chronic infection in mice, and isoniazid and RelMtb inhibitor candidates were tested for synergy against nutrient-starved wild-type Mtb and Δrel using checkerboard assays. The minimum bactericidal concentration of isoniazid was 500-fold lower against Δrel relative to wild type during nutrient starvation, and the potent bactericidal activity of isoniazid was maintained against Δrel during chronic infection in the lungs of mice. Inhibition of RelMtb appears to be a promising new approach to target Mtb persisters, with the potential to shorten the duration of treatment for drug-susceptible and drug-resistant TB. We used microarray to characterize the transcriptomic profiles of the wild type and Δrel during nutrient starvation. The RelMtb inhibitor, (E)-4-(3-methyl-4-(2-(4-methylthiazol-5-yl)ethoxy)styryl)benzoic acid, killed wild-type Mtb and prevented isoniazid tolerance during nutrient starvation. Treatment of nutrient-starved wild-type with the RelMtb inhibitor led to downregulation of the RelMtb regulon. Transcriptomic analysis revealed an altered gene expression in Δrel and wild-type treated with RelMtb inhibitor during nutrient starvation.

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Mycobacterium tuberculosis HN878 transcriptomes from replicating broth culture, THP1 macrophage-like cells, caseum surrogate, and rabbit caseum

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