4 research outputs found
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Beyond Mutation: Epigenetic Drivers of Phenotypic Diversity and Survival in Mycobacteria
M. tuberculosis is the causative agent of a global health epidemic that kills ~1.5 million people each year. The outcomes of infection with Mtb are highly variable. Although many patients are able to control the infection in a quiescent state, others develop active disease. Furthermore, the progression of TB lesions has been shown to vary within a single individual. This phenotypic variability in the infecting population of Mtb may be responsible for the high rate of treatment failures, which can exceed 20% in some endemic areas (World Health Organization, 2015). Although genetic mutation can drive a portion of the observed phenotypic variability, mutation rates in mycobacteria are exceedingly low. Epigenetic factors are therefore likely to be responsible for the majority of observed diversity in infection and treatment outcomes.
Here, we investigated epigenetic drivers of phenotypic variability and survival in mycobacteria. We found evidence of high rates of phenotypic variability in response to drug treatment of M. smegmatis, a non-pathogenic, model for TB. Specifically, we found that two distinct subpopulations are able to grow in the presence of drug. These subpopulations exhibited heritability of their transcriptional profiles, growth properties, and ability to grow on drug across generations. We next found that hupB, a histone-like protein, is critical for the formation of these epigenetically regulated subpopulations. We also show that hupB regulates gene expression and is post-translationally modified, and that modification of hupB may drive the formation of one of these phenotypically drug-resistant subpopulations. These findings suggest that modification of a histone-like protein may drive epigenetic inheritance and phenotypic variability in mycobacteria, which allows it to withstand antibiotic treatment. Finally, we also investigated alternative post-transcriptional mechanisms of hupB regulation.Biological Sciences in Public Healt
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The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
ABSTRACT This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies
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Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria
There is increasing evidence that phenotypically drug-resistant bacteria may be important determinants of antibiotic treatment failure. Using high-throughput imaging, we defined distinct subpopulations of mycobacterial cells that exhibit heritable but semi-stable drug resistance. These subpopulations have distinct transcriptional signatures and growth characteristics at both bulk and single-cell levels, which are also heritable and semi-stable. We find that the mycobacterial histone-like protein HupB is required for the formation of these subpopulations. Using proteomic approaches, we further demonstrate that HupB is posttranslationally modified by lysine acetylation and lysine methylation. Mutation of a single posttranslational modification site specifically abolishes the formation of one of the drug-resistant subpopulations of cells, providing the first evidence in prokaryotes that posttranslational modification of a bacterial nucleoid-associated protein may epigenetically regulate cell state