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Quantitative Proteomics Reveals Novel Insights into Isoniazid Susceptibility in Mycobacteria Mediated by a Universal Stress Protein
journal contribution
posted on 2015-03-06, 00:00 authored by Xinling Hu, Xiaojing Li, Lige Huang, John Chan, Yuling Chen, Haiteng Deng, Kaixia MiTuberculosis
(TB) is caused by the ancient pathogen, Mycobacterium
tuberculosis, and is one of the most
serious infectious diseases in the world. Isoniazid (INH) is an important
first-line drug for the treatment of active and latent TB. INH resistance
is an increasing problem in the treatment of TB. Phenotypic resistance
to INH, however, is poorly understood. In this study, we constructed
a strain of Mycobacterium bovis BCG
that overexpresses the latency-related universal stress protein (USP),
BCG_2013, and designated this strain BCG-2013. BCG_2013 overexpression
increased susceptibility to INH compared with that of the wild-type
strain, BCG-pMV261. Quantitative proteomic analysis revealed that
BCG_2013 overexpression resulted in the upregulation of 50 proteins
and the downregulation of 26 proteins among the 1500 proteins identified.
Upregulation of catalase-peroxidase KatG expression in BCG-2013 was
observed and confirmed by qPCR, whereas expression of other INH resistance-related
proteins did not change. In addition, differential expression of the
mycobacterial persistence regulator MprA and its regulatory proteins
was observed. BCG_2013 and katG mRNA
levels increased in a Wayne dormancy model, whereas MprA mRNA levels decreased. Taken together, our results suggest that the increase
in KatG levels induced by increased BCG_2013 levels underlies the
phenotypic susceptibility of mycobacteria to INH.
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Keywords
phenotypic susceptibilityPhenotypic resistancestress proteinINH resistanceWayne dormancy modelMprA mRNA levelsNovel Insights50 proteins26 proteins1500 proteinsQuantitative ProteomicsexpressionMycobacterium tuberculosisKatG levelsMycobacteria Mediatedmycobacterial persistence regulator MprAstrainUSPIsoniazid SusceptibilityMycobacterium bovis BCGTBUniversal Stress ProteinTuberculosiskatG mRNA levels
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