The therapeutic potential of epigenetic manipulation during infectious diseases

Morris, Paul D; Dickman, Mark J.; Dockrell, David H.

doi:10.1016/j.pharmthera.2016.07.013

Cited by 43 publications

(32 citation statements)

References 176 publications

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“…We recently reported that the methylation of genes in immune and inflammation domains in white blood cells (WBC) differed significantly between HIV-infected and uninfected individuals 19 . These findings and others suggest that disease outcomes might be worsened by epigenetic effects of comorbid addictions and, by implication, improved by treatments that target epigenetic processes 20 , 21 .…”

Section: Introductionmentioning

confidence: 70%

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty

Zhang

Justice

et al. 2017

Nat Commun

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Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) commonly co-occur among HIV-infected individuals. These co-occurring conditions may produce interacting epigenetic effects in white blood cells that influence immune function and health outcomes. Here, we report an epigenome-wide association analysis comparing IDU+/ HCV+ and IDU−/HCV− in 386 HIV-infected individuals as a discovery sample and in 412 individuals as a replication sample. We observe 6 significant CpGs in the promoters of 4 genes, NLRC5, TRIM69, CX3CR1, and BCL9, in the discovery sample and in meta-analysis. We identify 19 differentially methylated regions on chromosome 6 harboring MHC gene clusters. Importantly, a panel of IDU+/HCV+-associated CpGs discriminated HIV frailty based upon a validated index with an area under the curve of 79.3% for high frailty and 82.3% for low frailty. These findings suggest that IDU and HCV involve epigenetic programming and that their associated methylation signatures discriminate HIV pathophysiologic frailty.

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Section: Introductionmentioning

confidence: 70%

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty

Zhang

Justice

et al. 2017

Nat Commun

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“…Interestingly, a significant decrease in the ability of type I IFN to drive expression of these genes was observed in Huh-7 cells, but not in Hela cells in vitro , indicating that LDs may play a role in the IFN induction of ISGs in a cell type specific manner. Although the production of IFN is induced in essentially all cell types, the induction of some ISGs has been shown to be more cell-type specific [ 47 ]. The two cell lines utilised in this study contain different basal levels of LDs, and this can visualised in Fig 1A , where it can be seen that the hepatocyte cell line, Huh-7, has an abundance of LDs [ 46 ], in contrast to HeLa cells which do not contain plenteous amounts [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Lipid droplet density alters the early innate immune response to viral infection

et al. 2018

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The cellular localisation of many innate signalling events following viral infection has yet to be elucidated, however there has been a few cases in which membranes of certain cellular organelles have acted as platforms to these events. Of these, lipid droplets (LDs) have recently been identified as signalling platforms for innate TLR7 and 9 signalling. Despite their wide range of similar roles in various metabolic pathways, LDs have been overlooked as potential platforms for antiviral innate signalling events. This study established an in vitro model to evaluate the efficiency of the early innate immune response in cells with reduced LD content to the viral mimics, dsDNA and dsRNA, and Sendai viral infection. Using RT-qPCR, the expression of IFN-β and IFN-λ was quantified following stimulation along with the expression of specific ISGs. Luciferase based assays evaluated the combined expression of ISRE-promoter driven ISGs under IFN-β stimulation. Cellular LD content did not alter the entry of fluorescently labelled viral mimics into cells, but significantly decreased the ability of both Huh-7 and HeLa cells to produce type I and III IFN, as well as downstream ISG expression, indicative of an impeded innate immune response. This observation was also seen during Sendai virus infection of HeLa cells, where both control and LD reduced cells replicated the virus to the same level, but a significantly impaired type I and III IFN response was observed in the LD reduced cells. In addition to altered IFN production, cells with reduced LD content exhibited decreased expression of specific antiviral ISGs: Viperin, IFIT-1 and OAS-1 under IFN-β stimulation; However the overall induction of the ISRE-promoter was not effected. This study implicates a role for LDs in an efficient early innate host response to viral infection and future work will endeavour to determine the precise role these important organelles play in induction of an antiviral response.

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“…In humans, there are 18 different types of HDACs, which are divided into four classes based on their homology with yeast HDACs. All have proved useful in resolving inflammation, but also involve changes in the antibacterial capacity of macrophages [53]. Recent studies have elucidated the molecular mechanism by which primary response genes can be induced in a stimulus-dependent manner, despite their constitutive assembly into a chromatin structure resembling that found at active genes.…”

Section: "Epigenetic Drugs"mentioning

confidence: 99%

“…This pioneering development paves the way for a reversible modification of the epigenome and therefore, a specific approach to modifying cellular function by influencing gene expression without altering the underlying DNA. This could lead to the targeted resolution of inflammatory processes or the manipulation of individual epigenomes to reduce susceptibility to disease or prevent the relapse of malignant tumours [53]. In conclusion, the development of HDAC inhibitors, bromodomain inhibitors and CRISPR technology offers powerful tools with the potential to modulate the PTM of histones that regulates gene transcription for the management of infectious diseases.…”

Section: "Epigenetic Drugs"mentioning

confidence: 99%

Epigenetics and Infectious Disease: State-of-the-Art and Perspectives in New Generation Therapies

Maddaloni¹,

Daniela²,

Francesca³

et al. 2018

obm genet

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Infectious diseases are one of the most important causes of morbidity and mortality around the world and have a substantial impact on the health of communities. These diseases are caused by pathogenic microorganisms, such as bacteria, viruses, parasites and fungi. The antibiotics that are currently available are generally considered to be safe and well-tolerated. However antimicrobial resistance is an increasingly serious concern in the treatment of infectious diseases. An understanding of epigenetics now contributes significantly to the diagnosis and treatment of complex clinical disorders: epigenetics of the hosts can also explain the diversity in their responses to some infectious diseases due to microbes that escape the immunological system of the host. The new generation therapy with epigenetic drugs is here proposed as a useful tool in the fight against infective diseases.

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The therapeutic potential of epigenetic manipulation during infectious diseases

Cited by 43 publications

References 176 publications

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty

Lipid droplet density alters the early innate immune response to viral infection

Epigenetics and Infectious Disease: State-of-the-Art and Perspectives in New Generation Therapies

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