scholarly journals Persistent DNA Hyper-methylation Dampens Host Anti-Mycobacterial Immunity

2019 ◽  
Author(s):  
Andrew R. DiNardo ◽  
Kimal Rajapakshe ◽  
Tomoki Nishiguchi ◽  
Godwin Mtetwa ◽  
Qiniso Dlamini ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Methylation Status ◽  
Host Immunity ◽  
Immune Responsiveness ◽  
Chronic Infections ◽  
Household Contacts ◽  
Full Complement ◽  
Ifn Γ ◽  
Specific Immune Responsiveness

AbstractMycobacterium tuberculosis (Mtb) has co-evolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to shorten existing therapy and improve outcomes will require identifying the full complement by which host immunity is inhibited. Perturbing host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, LCMV and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of TB patients and their asymptomatic household contacts demonstrating that TB patients have DNA hyper-methylation of the IL-2-STAT5, TNF-NF-ϰB and IFN-γ signaling pathways. By MSRE-qPCR, multiple genes of the IL-12-IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1 and JAK2) were hyper-methylated in TB patients. The DNA hyper-methylation of these pathways is associated with decreased immune responsiveness with decreased mitogen induced upregulation of IFN-γ, TNF, IL-6 and IL-1β production. The DNA hyper-methylation of the IL-12-IFN-γ pathway was associated with decreased IFN-γ induced gene expression and decreased IL-12 inducible up-regulation of IFN-γ. This work demonstrates that immune cells from TB patients are characterized by DNA hyper-methylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and non-specific immune responsiveness.

scholarly journals Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-γ) Promoter and Subsequent Downregulation of IFN-γ Production

1998 ◽  
Vol 18 (9) ◽  
pp. 5166-5177 ◽  
Author(s):  
Judy A. Mikovits ◽  
Howard A. Young ◽  
Paula Vertino ◽  
Jean-Pierre J. Issa ◽  
Paula M. Pitha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Methylation Status ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1 ◽  
De Novo Methylation

ABSTRACT The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12, tumor necrosis factor alpha, and gamma interferon (IFN-γ), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-γ, a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-γ gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV-1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-γ gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-γ gene, and increased IFN-γ production, demonstrating a direct link between methyltransferase and IFN-γ gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-γ gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

scholarly journals A differential DNA methylome signature of pulmonary immune cells from individuals converting to latent tuberculosis infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lovisa Karlsson ◽  
Jyotirmoy Das ◽  
Moa Nilsson ◽  
Amanda Tyrén ◽  
Isabelle Pehrson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Methylation Status ◽  
Latent Tuberculosis ◽  
Metabolic Reprogramming ◽  
Dna Methylome ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Latent Tb ◽  
Latent Tb Infection

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary-resident immune cells. The role of epigenetic regulations in the immune cells is emerging and we have previously shown that macrophages capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in alveolar macrophages and T cells in a cohort of medical students with an increased risk of TB exposure, longitudinally. DNA methylome analysis revealed that a unique DNA methylation profile was present in healthy subjects who later developed latent TB during the study. The profile was reflected in a different overall DNA methylation distribution as well as a distinct set of differentially methylated genes (DMGs). The DMGs were over-represented in pathways related to metabolic reprogramming of macrophages and T cell migration and IFN-γ production, pathways previously reported important in TB control. In conclusion, we identified a unique DNA methylation signature in individuals, with no peripheral immune response to M. tuberculosis antigen who later developed latent TB. Together the study suggests that the DNA methylation status of pulmonary immune cells can reveal who will develop latent TB infection.

Host responses toMycobacterium aviumsubsp.paratuberculosis: a complex arsenal

2006 ◽  
Vol 7 (1-2) ◽  
pp. 61-70 ◽  
Author(s):  
J. R. Stabel
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Host Immunity ◽  
Host Responses ◽  
Clinical State ◽  
Cell Mediated Immunity ◽  
First Line ◽  
Activated T Cells ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

The immune system is not always successful in recognizing and destroying pathogens it may encounter. Host immunity to mycobacteria is characterized by a very complex series of events, designed to clear the infection. The first line of defense is uptake and processing of the pathogen by macrophages, followed by the initiation of cell-mediated immunity. The secretion of pro-inflammatory cytokines such as IFN-γ is credited with containment of mycobacterial infections. Yet it is clear that activated T-cells may contain but fail to clear the infection in some hosts. Further, it is recognized that if infection progresses to a more clinical state, the production of pro-inflammatory cytokines is suppressed and expression of anti-inflammatory cytokines is increased. It is unclear what defines a host that can successfully contain the infection versus one that succumbs to severe immunopathologic disease. This review will address some of the key elements in host immunity to mycobacterial pathogens, with an emphasis onMycobacterium aviumsubsp.paratuberculosis(M. paratuberculosis), in an attempt to understand the dialogue between immune cells and their mediators during infection and what causes this discourse to go awry.

scholarly journals A Differential DNA Methylome Signature of Pulmonary Immune Cells from Individuals Converting to Latent Tuberculosis Infection

2021 ◽  
Author(s):  
Lovisa Karlsson ◽  
Jyotirmoy Das ◽  
Moa Nilsson ◽  
Amanda Tyren ◽  
Isabelle Pehrson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Methylation Status ◽  
Latent Tuberculosis ◽  
Dna Methylome ◽  
T Cell Migration ◽  
Increased Risk ◽  
Before And After ◽  
Methylome Analysis ◽  
Latent Tb

Tuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary resident immune cells. The role of epigenetic regulations through DNA methylation in the immune cells is emerging. We have previously shown that capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in the pulmonary immune cells in a cohort of medical students with a previously documented increased risk of TB exposure, longitudinally. Sputum samples containing alveolar macrophages (AMs) and T cells were collected before and after study subjects worked in hospital departments with a high-risk of TB exposure. DNA methylome analysis revealed that a unique DNA methylation profile was present already at inclusion in subjects who developed latent TB during the study. The profile was both reflected in different overall DNA methylation distribution as well as more profound alterations in the methylation status of a unique set of CpG-sites. Over-representation analysis of the DMGs showed enrichment in pathways related to metabolic reprograming of macrophages and T cell migration and IFN-γ production. In conclusion, we identified a unique DNA methylation signature in individuals, while still IGRA-negative and who later developed latent TB. Epigenetic regulation was found in pathways that have previously been reported to be important in TB. Together the study suggests that DNA methylation status of pulmonary immune cells can predict IGRA conversion.

DNA Methylation Status of Mash2 in Lungs of Somatic Cell Cloning Bovines*

2010 ◽  
Vol 37 (9) ◽  
pp. 960-966 ◽  
Author(s):  
Jie CHEN ◽  
Dong-Jie LI ◽  
Cui ZHANG ◽  
Ning LI ◽  
Shi-Jie LI
Keyword(s):  
Dna Methylation ◽  
Somatic Cell ◽  
Methylation Status ◽  
Cell Cloning

Immunobiological Markers in Prophylaxis Post-exposure with Single Dose of Rifampicin and BCG Vaccine in Contacts of Multibacillary Leprosy Cases: Study Protocol (Preprint)

2020 ◽  
Author(s):  
Camila Massae Sato ◽  
Omar Ariel Espinosa Domínguez ◽  
Gutembergue Santos de Sousa ◽  
Fabiane Verônica da Silva ◽  
Roberta Olmo Pinheiro ◽  
...  
Keyword(s):  
Single Dose ◽  
Bcg Vaccine ◽  
Reference Laboratory ◽  
Serological Response ◽  
Bacillus Calmette Guerin ◽  
Prophylactic Measure ◽  
Mato Grosso ◽  
Household Contacts ◽  
Ifn Γ ◽  
Multibacillary Leprosy

BACKGROUND Leprosy contacts are sensitive indicator of the magnitude of severity, and a high risk for infection and disease, especially if the individuals are exposed to the bacillus with multibacillary cases, which reinforces the need for chemoprophylactic measures, such as the use single-dose rifampicin (SDR) combined with BCG vaccine. OBJECTIVE Our study will analyze the serological response of anti-NDO-LID, HO-1/HMOX and serum IFN-γ concentration as a prophylactic measure after the use of single-dose rifampicin (SDR) combined with the Bacillus Calmette-Guérin vaccine (BCG) among multibacillary leprosy household contacts. METHODS Intervention study based on a prospective cohort of household contacts of new cases of multibacillary leprosy diagnosed and registered in the Information System on Diseases of Compulsory Declaration (SINAN – Sistema de Informação de Agravos de Notificação) and residents in the municipalities of Cuiabá and Cáceres, Mato Grosso, in the years 2019 and 2020. Contacts with no signs and symptoms compatible with the disease of the intervention group will receive single-dose rifampicin (SDR) combined with BCG vaccine and will be compared to the control group. The follow-up of the cohort will last 12 months. The analyses of the anti-NDO-LID, HO-1/HMOX and serum concentration of IFN-γ tests as immunological markers before, 6 and 12 months after the intervention will be conducted in a reference laboratory (FIOCRUZ). RESULTS The study is still recruiting participants and is expected to be completed in September 2020. CONCLUSIONS Our study seeks to analyze the response of anti-NDO-LID, HO-1/HMOX tests and serum IFN-γ concentration as a prophylactic measure after the use of single-dose rifampicin (SDR) combined with the Bacillus Calmette-Guérin vaccine (BCG) in home contacts of multibacillary leprosy cases. CLINICALTRIAL Brazilian Registry of Clinical Trials (ReBEC), RBR-6yg2z9. Retrospectively registered on 3 de Out. de 2019.

scholarly journals Epigenetic Changes During Mechanically Induced Osteogenic Lineage Commitment

2015 ◽  
Vol 137 (2) ◽  
Author(s):  
Julia C. Chen ◽  
Mardonn Chua ◽  
Raymond B. Bellon ◽  
Christopher R. Jacobs
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Shear Stress ◽  
Fluid Shear Stress ◽  
Methylation Status ◽  
Lineage Commitment ◽  
Fluid Shear ◽  
Osteogenic Lineage ◽  
Osteogenic Markers ◽  
Heterochromatin Structure

Osteogenic lineage commitment is often evaluated by analyzing gene expression. However, many genes are transiently expressed during differentiation. The availability of genes for expression is influenced by epigenetic state, which affects the heterochromatin structure. DNA methylation, a form of epigenetic regulation, is stable and heritable. Therefore, analyzing methylation status may be less temporally dependent and more informative for evaluating lineage commitment. Here we analyzed the effect of mechanical stimulation on osteogenic differentiation by applying fluid shear stress for 24 hr to osteocytes and then applying the osteocyte-conditioned medium (CM) to progenitor cells. We analyzed gene expression and changes in DNA methylation after 24 hr of exposure to the CM using quantitative real-time polymerase chain reaction and bisulfite sequencing. With fluid shear stress stimulation, methylation decreased for both adipogenic and osteogenic markers, which typically increases availability of genes for expression. After only 24 hr of exposure to CM, we also observed increases in expression of later osteogenic markers that are typically observed to increase after seven days or more with biochemical induction. However, we observed a decrease or no change in early osteogenic markers and decreases in adipogenic gene expression. Treatment of a demethylating agent produced an increase in all genes. The results indicate that fluid shear stress stimulation rapidly promotes the availability of genes for expression, but also specifically increases gene expression of later osteogenic markers.

scholarly journals DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jack Hearn ◽  
Fiona Plenderleith ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Daphnia Magna ◽  
Single Gene ◽  
Methylation Status ◽  
Strain Differences ◽  
Life History Trait ◽  
Food Level ◽  
Epigenetic Clock ◽  
Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

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