Macrophage responses to MDR M.tuberculosis infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE115495 | GEO | 2018/12/26
REPOSITORIES: GEO
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Project description:Macrophage responses to MDR M.tuberculosis infection
| PRJNA475201 | ENA
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.
2021-06-05 | GSE99710 | GEO
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs. New Zealand White rabbits were infected with Mtb HN878 or CDC1551 at ~3.5log10. At 3 hours post infection, lung tissue from Mtb-infected and uninfected rabbits were isolated and used for total RNA extraction. Total rabbit lung RNA was used for microarray analysis to determine infection induced changes in host gene expression.
2013-08-17 | E-GEOD-49947 | biostudies-arrayexpress
Project description:We examined the microRNA profiles of THP-1 macrophages upon the MTB infection of (1) Beijing/W and non-Beijing/W clinical strains, and (2) susceptible and multidrug-resistant (MDR-) MTB strains.
2015-07-01 | GSE65811 | GEO
Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), latently infects one quarter of the world’s population. The rise of multidrug resistant (MDR) Mtb infections worldwide presents a significant obstacle to curb TB globally. While human studies report dysregulated immune responses in MDR TB patients, there is a lack of clear understanding of the host-pathogen interactions following MDR Mtb infection. We recently showed that Mtb carrying a rifampicin drug resistance (RDR)-conferring single nucleotide polymorphism in the RNA polymerase-B gene (Mtb rpoB-H445Y) can modulate host macrophage metabolic reprogramming by production of Type I IFNs. Here, using a mouse model, we have characterized the host immune response in vivo following RDR Mtb infection. We show that despite establishment of Mtb infection in the lung and dissemination to the peripheral organs, lung myeloid and lymphoid immune responses to RDR Mtb is suppressed through a Type I IFN-dependent mechanism. These results coincide with a muted responses in the bone marrow hematopoietic stem and progenitor cells (HSPCs) and progenitors following RDR Mtb infection. These results suggest that host directed therapeutics and vaccines for drug resistant TB may need to be target specific host immune pathways for protection.
2022-06-01 | GSE176423 | GEO
Project description:We examined the microRNA profiles of THP-1 macrophages upon the MTB infection of (1) Beijing/W and non-Beijing/W clinical strains, and (2) susceptible and multidrug-resistant (MDR-) MTB strains. THP-1 cells were induced differentiation into a macrophage phenotype. Then cells were infected with three MDR (INHR, RIFR) Beijing/W, three sensitive (INHS, RIFS) Beijing/W, three MDR(INHR, RIFR) non-Beijing/W, and three sensitive (INHS, RIFS) non-Beijing/W strains. Total RNA were extracted and transfered into cDNA for miRNA profile analysis. Non-infected cells were used as control.
2015-07-01 | E-GEOD-65811 | biostudies-arrayexpress
Project description:Current antibiotic regimen to treat tuberculosis (TB) is ineffective in fully eliminating the bacterial load and in alleviating disease pathology. We examined the usefulness of a phosphodiesterase-4 inhibitor (CC-11050) as an adjunctive to anti-TB drug Isoniazid (INH) to improve the outcome of treatment in a rabbit model of active pulmonary TB. Control of Mycobacterium tuberculosis (Mtb) growth, disease pathology and the global transcriptional response in Mtb-infected lungs of rabbits with or without CC-11050 treatment were studied. The microarray experiments involves comparison of changes in gene expression between uninfected and Mtb-HN878 infected (Untreated) or CC-11050 treated rabbit lungs at 8 weeks post-treatment, starting at 4 weeks of infection (i.e, 12 weeks post infection).
2015-12-21 | GSE74687 | GEO
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs.
2013-08-17 | GSE49947 | GEO
Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1M-bM-^@M-^Ys activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs. Transcriptional profile of TCA1-treated cells relative to DMSO-treated control. Three biological replicates, third is a dye flip.
2013-05-24 | E-GEOD-42151 | biostudies-arrayexpress
Project description:Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) strains and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018-2021, obtained from the analysis of whole genome sequence data. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB (HR-MTB), 7 were resistant only to one antibiotic (3 were resistant only to ethambutol and 3 isolate to streptomycin while one isolate showed resistance to fluoroquinolones), 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB (pre-XDR). This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of TB infection.
2023-11-17 | E-MTAB-13058 | biostudies-arrayexpress