Epigenetics and innate immunity: the ‘unTolld’ story

Hennessy, Conor; McKernan, Declan P.

doi:10.1038/icb.2016.24

Cited by 23 publications

(12 citation statements)

References 121 publications

(202 reference statements)

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“…Self-healing of primary infections of P. chabaudi bloodstage malaria generates long-lasting immunity, which manifests itself as much lower parasitemias upon homologous rechallenge in comparison to the corresponding primary infections Wunderlich et al 2014). There is ample evidence that also genes involved in both innate and adaptive immunity are under complex epigenetic control including modifications of DNA methylation (Lim et al 2010;Rodriguez-Cortez et al 2011;Kondilis-Mangum and Wade 2013;Obata et al 2015;Hennessy and McKernan 2016). Insofar, it is rather surprising that protective vaccination and P. chabaudi infections induce changes in the DNA methylation of promoters of so many genes, most of them are related to regulation of transcription, but only very few genes can be related to any functions of the immune system inherent to the liver by gene set enrichment analyses.…”

Section: Discussionmentioning

confidence: 95%

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

et al. 2017

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Epigenetic mechanisms such as DNA methylation are increasingly recognized to be critical for vaccination efficacy and outcome of different infectious diseases, but corresponding information is scarcely available for host defense against malaria. In the experimental blood-stage malaria Plasmodium chabaudi, we investigate the possible effects of a blood-stage vaccine on DNA methylation of gene promoters in the liver, known as effector against blood-stage malaria, using DNA methylation microarrays. Naturally susceptible Balb/c mice acquire, by protective vaccination, the potency to survive P. chabaudi malaria and, concomitantly, modifications of constitutive DNA methylation of promoters of numerous genes in the liver; specifically, promoters of 256 genes are hyper(=up)- and 345 genes are hypo(=down)-methylated (p < 0.05). Protective vaccination also leads to changes in promoter DNA methylation upon challenge with P. chabaudi at peak parasitemia on day 8 post infection (p.i.), when 571 and 1013 gene promoters are up- and down-methylated, respectively, in relation to constitutive DNA methylation (p < 0.05). Gene set enrichment analyses reveal that both vaccination and P. chabaudi infections mainly modify promoters of those genes which are most statistically enriched with functions relating to regulation of transcription. Genes with down-methylated promoters encompass those encoding CX3CL1, GP130, and GATA2, known to be involved in monocyte recruitment, IL-6 trans-signaling, and onset of erythropoiesis, respectively. Our data suggest that vaccination may epigenetically improve parts of several effector functions of the liver against blood-stage malaria, as, e.g., recruitment of monocyte/macrophage to the liver accelerated liver regeneration and extramedullary hepatic erythropoiesis, thus leading to self-healing of otherwise lethal P. chabaudi blood-stage malaria.

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Section: Discussionmentioning

confidence: 95%

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

et al. 2017

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“…However, understanding this effect at the single-cell level has important conceptual implications that offer new therapeutic strategies to desensitize innate immunity in epithelial tissues and potentially impede the progression of chronic inflammation. Furthermore, considering that both innate and adaptive immunity are subject to epigenetic regulation 27,47 and are both dominated by digital signaling events, we propose that epigenetic switching could be a general mechanism for limiting tissue-or organism-level inflammation during the immune response. Fig.…”

Section: Discussionmentioning

confidence: 99%

Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level

et al. 2021

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To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.

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“…The epigenetic state of cells is believed to result in variation in innate responses among chickens and can determine the resistance/susceptibility patterns to pathogens (Gou et al, 2012). DNA methylation and histone modifications are important epigenetic modifications involving the promoter regions of pathogen sensors or signalling pathways leading to either activation or suppression of a series of immune responses (Gou et al, 2012;Hennessy & McKernan, 2016). While profiling innate responses in Salmonella enterica serovar Enteritidis susceptible and resistant birds, one study identified higher DNA methylation levels in the promoter region of TLR4 and TLR21 and in an exonic CpG island of TLR2-1 in the susceptible chickens (Gou et al, 2012).…”

Section: Epigenetic Control Of Innate Immunitymentioning

confidence: 99%

Development of innate immunity in chicken embryos and newly hatched chicks: a disease control perspective

et al. 2019

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Newly hatched chickens are confronted by a wide array of pathogenic microbes because their adaptive immune defences have limited capabilities to control these pathogens. In such circumstances, and within this age group, innate responses provide a degree of protection. Moreover, as the adaptive immune system is relatively naïve to foreign antigens, synergy with innate defences is critical. This review presents knowledge on the ontogeny of innate immunity in chickens pre-hatch and early post-hatch and provides insights into possible interventions to modulate innate responses early in the life of the bird. As in other vertebrate species, the chicken innate immune system which include cellular mediators, cytokine and chemokine repertoires and molecules involved in antigen detection, develop early in life. Comparison of innate immune systems in newly hatched chickens and mature birds has revealed differences in magnitude and quality, but responses in younger chickens can be boosted using innate immune system modulators. Functional expression of pattern recognition receptors and several defence molecules by innate immune system cells of embryos and newly hatched chicks suggests that innate responses can be modulated at this stage of development to combat pathogens. Improved understanding of innate immune system ontogeny and functionality in chickens is critical for the implementation of sound and safe interventions to provide long-term protection against pathogens. Next-generation tools for studying genetic and epigenetic regulation of genes, functional metagenomics and gene knockouts can be used in the future to explore and dissect the contributions of signalling pathways of innate immunity and to devise more efficacious disease control strategies.

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Epigenetics and innate immunity: the ‘unTolld’ story

Cited by 23 publications

References 121 publications

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level

Development of innate immunity in chicken embryos and newly hatched chicks: a disease control perspective

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