Dataset Information

Proteomics of Mycobacterium tuberculosis Beijing genotype after acquisition of Isoniazid resistance

ABSTRACT: This project provides the first characterization of protein differences in clinical isolates of Mtb after acquisition of resistance to isoniazid (INH), one of the most important drug treatment options against TB. This study determines the global protein differences in a clinical isogenic pair of Mtb, comparing INH susceptibility versus INH resistance.

INSTRUMENT(S): LTQ

ORGANISM(S): Mycobacterium Tuberculosis H37rv

TISSUE(S): Prokaryotic Cell

DISEASE(S): Pulmonary Tuberculosis

SUBMITTER: Luisa Nieto

LAB HEAD: Karen M. Dobos

PROVIDER: PXD002986 | Pride | 2016-03-14

REPOSITORIES: Pride

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Publications

Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: A proteomics approach.

Nieto R Luisa María LM Mehaffy Carolina C Dobos Karen M KM

Proteomics 20160413 9

We determined differences in the protein abundance among two isogenic strains of Mycobacterium tuberculosis (Mtb) with different Isoniazid (INH) susceptibility profiles. The strains were isolated from a pulmonary tuberculosis patient before and after drug treatment. LC-MS/MS analysis identified 46 Mtb proteins with altered abundance after INH resistance acquisition. Protein abundance comparisons were done evaluating the different bacterial cellular fractions (membrane, cytosol, cell wall and sec ...[more]

PMID: 26929115

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Project description:Tuberculosis kills nearly 2 million people through out the world, every year. The outcome of M. tuberculosis infection is determined by the host and bacterial factors. A strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including chemotaxis and proliferation of effector cells. The infecting bacilli counteracts the bactericidal activities of the host immune cells, primarily by modifying their gene expression. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. Tumor necrosis factor-alpha (TNF-a), produced by the immune cells, is an important cytokine in protecting the host against Mtb infection. However, excessive TNF-a production leads to severe inflammation and host cell destruction. In fact, pharmacologic inhibition of TNF-a production has been considered as a therapeutic modality in inflammatory diseases. Interestingly, inhibitors of host phosphodiesterase-4 (PDE4) have been shown to reduce TNF-a production and dampen inflammation without complete immune suppression of the host. In this study, we have explored the use of one of the PDE4 inhibitors, CC-3052, as an adjunct immune modulatory drug, in combination with isoniazid (INH) treatment in rabbit pulmonary tuberculosis. We hypothesize that reducing TNF-a levels during Mtb infection would reduce the environmental pressure on the bacteria, rendering them more amenable to killing by INH. Mtb infected rabbits were treated with CC-3052 or INH or both and the lung tissue were harvested after 4 and 8 weeks of treatment. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared between various treatment groups. The results of our study provides data to support the idea that combining anti-TB drugs with an adjunctive immune modulator may enhance the efficacy of current TB therapy regimens and shorten the duration of treatment if applied appropriately to humans. The microarray experiments involves 2 comparison groups. 1) Changes in rabbit gene expression between Mtb infected and uninfected animals; 2). Changes in rabbit gene expression between CC-3052 treated and untreated animals during Mtb infection at 4,8 and 12 weeks post infection. New Zealand White rabbits were infected with Mtb HN878 at 3.2log10 (on day 0). At 4 weeks post infection, one group of infected rabbits were treated with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, and the treatment was continued up to 12 weeks post infection. The compound was used at 25mg/kg body weight, dissolved in distilled water and administered through gavage five days a weeks. Lung tissue from Uninfected, Mtb-infected and Untreated or CC-3052 treated rabbits were isolated at Day0, 4,8 and 12 weeks post infection and used for total RNA extraction. Only the 8 and 12 week timepoints correspond to the associated publication.

Dataset Information

Proteomics of Mycobacterium tuberculosis Beijing genotype after acquisition of Isoniazid resistance

Publications

Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: A proteomics approach.

Similar Datasets

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