DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

Pehrson, Isabelle; Das, Jyotirmoy; N, Idh; Karlsson, Lovisa; Rylander, Harald; H, Hard af Segerstad; Reutersward, E; Marttala, E; Paues, Jakob; Méndez-Aranda, Melissa; Ugarte-Gil, César; Lerm, Maria

doi:10.1101/2021.03.16.21253725

Cited by 3 publications

(3 citation statements)

References 64 publications

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“…immune cell populations have been reported both in immune-related diseases and allergies (4) as well as infectious diseases (5-7). In line with this, we have observed that immune cells of asymptomatic, tuberculosis-exposed individuals carry a lasting DNAm biosignature (8-10) that is linked to protection against mycobacterial infection (8). However, epigenetic alterations can also be induced by pathogens for their own benefit (11-14).…”

Section: Introductionsupporting

confidence: 52%

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Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

Huoman

Sayyab

Apostolou

et al. 2021

Preprint

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Background: Coronaviruses such as SARS-CoV-2 may circumvent host defence mechanisms by hijacking host proteins, possibly by altering DNA methylation patterns in host cells. While most epigenetic studies have been performed in severely ill COVID-19 patients, studies on individuals who have recovered from mild-to-moderate disease remain scarce. The aim of this study was to assess epigenome-wide DNA methylation patterns in COVID-19 convalescents compared to uninfected controls from before and after the pandemic outbreak began. Methods: DNA was extracted from peripheral blood mononuclear cells originating from uninfected controls before (Pre20, n=5) and after (Con, n=18) 2020, COVID-19 convalescents (CC19, n=14) and symptom-free individuals with a SARS-CoV-2-specific T cell response (SFT, n=6), as well as from Pre20 (n=4) samples stimulated in vitro with SARS-CoV-2. Subsequently, epigenome-wide DNA methylation analyses were performed using the Illumina MethylationEPIC 850K array, and statistical and bioinformatic analyses comprised differential DNA methylation, pathway over-representation and module identification network analyses. Results: DNA methylation patterns of COVID-19 convalescents were altered as compared to uninfected controls, with similar results observed in in vitro stimulations of PBMC with SARS-CoV-2. Differentially methylated genes from the in vivo comparison constituted the foundation for the identification of a possibly SARS-CoV-2-induced module, containing 66 genes of which six could also be identified in corresponding analyses of the in vitro data (TP53, INS, HSPA4, SP1, ESR1 and FAS). Pathway over-representation analyses revealed involvement of Wnt, cadherin and apoptosis signalling pathways amongst others. Furthermore, numerous interactions were found between the obtained differentially methylated genes from both settings and the network analyses when overlaying the data unto the SARS-CoV-2 interactome. Conclusions: Epigenome-wide DNA methylation patterns of individuals that have recovered from mild-to-moderate COVID-19 are different from those of non-infected controls. The observed alterations during both in vivo and in vitro exposure to SARS-CoV-2 showed involvement in interactions and pathways that are highly relevant to COVID-19. The present study provides indications that DNA methylation is one of several epigenetic mechanisms that is altered upon SARS-CoV-2 infection. Further studies on the mechanistic underpinnings should determine whether the observed effects are reflecting host-protective antiviral defence or targeted viral hijacking to evade host defence.

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Section: Introductionsupporting

confidence: 52%

“…15-17 In line with this, we have previously observed that immune cells of asymptomatic, tuberculosis-exposed individuals carry a lasting DNAm signature that is linked to protection against mycobacterial infection. 18-20…”

Section: Introductionmentioning

confidence: 99%

Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

Huoman

Sayyab

Apostolou

et al. 2021

Preprint

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“…The observations made with IGRA converters were limited to two study subjects. However, we recently published a study that supports the finding of a differential DNA methylation pattern that can distinguish individuals with latent TB from IGRA-negative individuals in a similar high endemic setting in Lima, Peru 46 (MedRxiv pre-print, 2021). We also recently showed that M. tuberculosis exposure-induced epigenetic reprogrammings are more profound in pulmonary immune cells as compared to PBMCs 47 (MedRxive pre-print 2021).…”

Section: Discussionmentioning

confidence: 79%

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

Karlsson

Das

Nilsson

et al. 2021

Sci Rep

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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 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.

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Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2in vivoandin vitro

et al. 2022

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A majority of SARS-CoV-2 recoverees develop only mild-to-moderate symptoms, while some remain completely asymptomatic. Although viruses, including SARS-CoV-2, may evade host immune responses by epigenetic mechanisms including DNA methylation, little is known about whether these modifications are important in defence against and healthy recovery from COVID-19 in the host. To this end, epigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents, and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated in vitro with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation, and module identification analyses. Differential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified in vivo , comprising 66 genes of which six ( TP53, INS, HSPA4, SP1, ESR1, and FAS ) were present in corresponding in vitro analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling, and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. Altered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. Both in vitro and in vivo exposure caused epigenetic modulation of pathways thataffect odour perception. Future studies should determine whether this reflects host-induced protective antiviral defense or targeted viral hijacking to evade host defence.

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DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

Cited by 3 publications

References 64 publications

Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

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

Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2in vivoandin vitro

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