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Multiplatform, non-targeted analysis of lung extracts of uninfected and Mtb-infected C57BL/6 mice at 4 and 9 weeks p.i.

ABSTRACT: The goal of this multiplatform, non-targeted metabolomics study was to explore the metabolic alterations occurring during the natural progression of pulmonary tuberculosis in a murine model of disease (C57BL/6 genotype). For this purpose, we used gas chromatography, capillary electrophoresis, and reversed-phase liquid chromatography coupled to high-resolution mass analyzers (GC-EI-QTOF/MS, CE-ESI(+)-QTOF/MS, LC-ESI(+)-QTOF/MS and LC-ESI(-)-QTOF/MS to analyze lung extracts of age and sex-matched uninfected mice (UW, n=4), Mycobacterium tuberculosis-infected mice at 4 weeks post-infection (4W, n=4) and Mycobacterium tuberculosis-infected mice at 9 weeks post-infection. All data were acquired in MS1 mode, following a canonical non-targeted workflow.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Lung

DISEASE(S): Tuberculosis

SUBMITTER: Miguel Fernandez Garcia

PROVIDER: ST001328 | MetabolomicsWorkbench | Thu Mar 12 00:00:00 GMT 2020

REPOSITORIES: MetabolomicsWorkbench

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Project description:Iron is critical for the survival of both the host and pathogens. Dysregulated iron metabolism is reported in tuberculosis patients, and therefore represents an opportunity for developing host-directed therapeutics. In this study, antimycobacterial properties of an iron chelator, i.e. Deferoxamine (DFO) and its impact on the transcriptomic changes in Mycobacterium tuberculosis (Mtb) and its impact on limiting host iron in C57BL/6 mice were explored. A group of mice received ferric carboxymaltose to create an iron overload condition and were aerosol infected with H37Rv Mtb. Mtb-infected mice received isoniazid (INH) and rifampicin (RIF) with or without DFO for tissue CFU assay, liver metabolite, iron quantification using GC-MS and ICP-MS, respectively. DFO showed comparable antimycobacterial properties like INH in in-vitro conditions. DFO-treatment deregulated 137 transcript levels in Mtb and majority were involved in stress response, encoding iron-containing proteins and downregulation of genes involved in essential vitamins and amino acid metabolism. Iron-overloaded mice exhibited significantly higher tissue mycobacterial burden at two weeks post-infection and the efficacy of INH and RIF were compromised. Iron chelation by DFO significantly reduced the tissue mycobacterial burden at 4 weeks post-treatment and, as an adjunct to INH and RIF, significantly lowered lung mycobacterial load within the first and second weeks of treatment compared to the group that received only INH and RIF. The intracellular pro-inflammatory cytokine levels in the lung CD4+ T-cells of INH and RIF-treated groups with or without DFO were found to be similar. DFO with RIF and INH treatment significantly altered liver arginine biosynthesis, which has a direct role in neutralizing ammonia and has an immune-supportive role. Currently, DFO is used for treating acute iron toxicity and in iron-overloaded thalassemic patients and holds promise as adjunct therapeutics for tuberculosis.

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Multiplatform, non-targeted analysis of lung extracts of uninfected and Mtb-infected C57BL/6 mice at 4 and 9 weeks p.i.

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