Methylation in Mycobacterium-host interaction and implications for novel control measures

Asaad, Mohammed; Abo-Kadoum, M. A.; Lambert, Nzungize; Uae, Moure; Nzaou, Stech A.E.; Xie, Jianping

doi:10.1016/j.meegid.2020.104350

Cited by 6 publications

(4 citation statements)

References 58 publications

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“…A second potential explanation for non-exact replication across cohorts may be exposure to different Mycobacterial lineages and/or environmental differences, such as cooking method, that may affect cellular phenotype. This study does not distinguish between methylation differences induced by Mtb stimulation, which has been shown by other studies [17, 19, 35, 36] versus inherent differences between individuals with TB or LTBI. An alternative hypothesis may be that subjects who resist development of TB respond to Mtb-induced methylation differently; future studies are needed to distinguish these hypotheses.…”

Section: Discussionmentioning

confidence: 80%

“…Host factors play an important role in the progression from LTBI to active TB disease, including genetic and transcriptomic factors [4, 14]. To our knowledge, only two small methylome-wide studies have been published [15, 16] in human cohorts, though in vitro studies have been conducted [17-19]. Our analysis of TB patient cohorts from Uganda and Tanzania revealed three regions that were differentially methylated in HIV-infected individuals who exhibited protection from active TB.…”

Section: Discussionmentioning

confidence: 99%

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Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

Stein

Bencheck

Bartlett

et al. 2020

Preprint

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Background: Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world, especially sub-Saharan Africa. Even though a third of humans are exposed to Myocbacterium tuberculosis (Mtb), most infected immunocompetent individuals do not develop active TB. In contrast, for individuals infected with both TB and the human immunodeficiency virus (HIV), the risk of active disease is 10% or more per year. Previously, we identified in a genome-wide association study a region on chromosome 5 that was associated with resistance to TB. This region included epigenetic marks that could influence gene regulation so we hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB. To test this hypothesis, we conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania. Results: In 221 HIV-infected adults from Uganda and Tanzania, we identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls, that also included methylation QTLs and associated SNPs: chromosome 1 (RNF220, p=4x10-5), chromosome 2 (between COPS8 and COL6A3 genes, p=2.7x10-5), and chromosome 5 (CEP72, p=1.3x10-5). These methylation results colocalized with associated SNPs, methylation QTLs, and methylation x SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. Conclusion: Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

Stein

Bencheck

Bartlett

et al. 2020

Preprint

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“…A major focus of epigenetics is the description of chromatin structure, DNA modifications by methylation and modifications of histones, and the link of these changes with gene expression [56][57][58]. In the context of human tuberculosis patients, most studies have been concerned with gene expression changes in blood cells due to M. tuberculosis without additional characterisation of underlying DNA or chromatin changes.…”

Section: Human Biomarkers Derived From the Systems Biology Approaches Human Genetics And Epigenomics In The Management Of Patients With Tmentioning

confidence: 99%

Perspectives for systems biology in the management of tuberculosis

et al. 2021

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Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches – human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics, immunophenotyping, systems pharmacology and gut microbiomes – in the management of tuberculosis including prediction of risk for disease progression, severity of mycobacterial virulence and drug resistance, adverse events, comorbidities, response to therapy and treatment outcomes. Application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach demonstrated that at present most of the studies provide “very low” certainty of evidence for answering clinically relevant questions. Further studies in large prospective cohorts of patients, including randomised clinical trials, are necessary to assess the applicability of the findings in tuberculosis prevention and more efficient clinical management of patients.

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“…For instance, methylation at histone 3 lysine 9 residue trimethylation (H3K9me3) is associated with repression and histone 3 lysine 4 residue trimethylation (H3K4me3) with activation of DNA complex [63,64]. These modifications which include global methylation within the genome, control cell signaling, alter the host histones, and even acts upon the BCG vaccine response [65].…”

Section: Histone Methylationmentioning

confidence: 99%

Epigenetic code during mycobacterial infections: therapeutic implications for tuberculosis

et al. 2021

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Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium tuberculosis (M.tb) uses epigenetics as a tool to protect itself from the host immune system. TB is a deadly disease-causing maximum death per year due to a single infectious agent. In the case of TB, there is an urgent need for novel host-directed therapies which can effectively target the survival and long term persistence of the bacteria without developing drug resistance in the bacterial strains while also reducing the duration and toxicity associated with the mainstream anti-TB drugs. Recent studies have suggested that TB infection has a significant effect on the host epigenome thereby manipulating the host immune response in the favor of the pathogen. M.tb alters the activation status of key genes involved in the immune response against TB to promote its survival and subvert the antibacterial strategies of the host. These changes are reversible and can be exploited to design very efficient host-directed therapies to fight against TB. This review has been written with the purpose of discussing the role of epigenetic changes in TB pathogenesis and the therapeutic approaches involving epigenetics, which can be utilized for targeting the pathogen.

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Methylation in Mycobacterium-host interaction and implications for novel control measures

Cited by 6 publications

References 58 publications

Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

Perspectives for systems biology in the management of tuberculosis

Epigenetic code during mycobacterial infections: therapeutic implications for tuberculosis

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