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Convergent evolution dictates that diverse groups of viruses will target both similar and distinct host pathways to manipulate the immune response and improve infection. In this study, we sought to leverage this uneven viral antagonism to identify critical host factors that govern disease outcome. Utilizing a systems-based approach, we examined dif...
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Citations
... significant changes to the host chromatin, including altering gDNA methylation and histone modifications, and in some cases, chromatin structure 8,13,19 . These studies suggest that viral-induced changes to chromatin structure and alteration of host (and virus) epigenetic modifications aids in the progression of infection. ...
The genome folds into complex configurations and structures thought to profoundly impact its function. The intricacies of this dynamic structure-function relationship are not well understood particularly in the context of viral infection. To unravel this interplay, here we provide a comprehensive investigation of simultaneous host chromatin structural (via Hi-C and ATAC-seq) and functional changes (via RNA-seq) in response to vaccinia virus infection. Over time, infection significantly impacts global and local chromatin structure by increasing long-range intra-chromosomal interactions and B compartmentalization and by decreasing chromatin accessibility and inter-chromosomal interactions. Local accessibility changes are independent of broad-scale chromatin compartment exchange (~12% of the genome), underscoring potential independent mechanisms for global and local chromatin reorganization. While infection structurally condenses the host genome, there is nearly equal bidirectional differential gene expression. Despite global weakening of intra-TAD interactions, functional changes including downregulated immunity genes are associated with alterations in local accessibility and loop domain restructuring. Therefore, chromatin accessibility and local structure profiling provide impactful predictions for host responses and may improve development of efficacious anti-viral counter measures including the optimization of vaccine design.
... The copyright holder for this preprint this version posted November 17, 2023. ; https://doi.org/10.1101/2023.11.15.567280 doi: bioRxiv preprint RNA viruses such as SARS-CoV-2, may impart significant changes to the host chromatin, including altering gDNA methylation and histone modifications, and in some cases, chromatin structure 8,13,19 . These studies suggest that viral-induced changes to chromatin structure and alteration of host (and virus) epigenetic modifications aids in the progression of infection. ...
Genomic DNA folds into complex configurations that produce particular local and global structures thought to profoundly impact genome function. To understand the dynamic nature of this relationship, we investigated the extent of host chromatin structural and functional changes in response to a viral agent. We performed comprehensive assessments of host architecture (Hi-C), accessibility (ATAC-seq), and gene expression (RNA-seq) in a paired manner in response to attenuated vaccinia (smallpox) virus. Over time, infection significantly increased long-range intra-chromosomal interactions and decreased chromatin accessibility. Fine-scale accessibility changes were independent of broad-scale chromatin compartment exchange, which increased (up to 12% of the genome) over time, underscoring potential independent mechanisms for global and local chromatin reorganization. The majority of differentially expressed genes, including those downregulated in immune responses, had concurrent alterations in local accessibility and loop domain restructuring. Increased B compartmentalization, intra-chromosomal interactions, and decreased inter-chromosomal interactions and chromatin accessibility together indicate that infection converts the host genome into a more condensed state with nearly equal bidirectional differential gene expression. These changes in host chromatin features may have implications for developing efficacious anti-viral countermeasures. Overall, our empirical data provides evidence of orchestrated concurrent alterations in chromatin architecture, accessibility, and gene expression in response to infection, further reinforcing the notion of coordinated structure-function dynamics of the genome.
... These viral factors include the negative regulatory factor (Nef) in HIV-1 [16], the MCMV-encoded glycoprotein gp48 [17], and the adenovirus early protein E1A [18]. Recent studies also reported that H5N1 influenza (H5N1-VN1203) and the Middle East respiratory syndrome (MERS)-CoV suppress the expression of MHC class I genes, through modulating epigenetic regulation of the MHC class I gene locus [19]. ...
... Such patients most commonly have medical signs of nausea, dry cough, dyspnea, and two-sided imaging lung infiltration. These patients were all related to Wuhan's HUANAN SEAFOOD comprehensive market, which sells fish as well as a number of live animals, comprising chickens, snakes, birds, and marmots [69]. The contributory cause was reported from the throat gauze tests collected by the CCDC on January 7th, 20 and consequently labeled SARS-Covid-2. ...
... Corley et al., described how, in severe cases of COVID-19, the epigenetic changes in immune cells varied and DNA methylation decreased in primary neutrophils [79]. Yes [77][78][79] Yes [74] Yes [81,82] Yes [64] Yes [83] Non-coding RNA Yes [80] Yes [74] Changes in DNA acetylation Yes [68] Not Identified Not Identified Yes [81] Not Identified Not Identified ...
Epigenetics generally involves genetic control by factors other than our own DNA sequence. Recent research has focused on delineating the mechanisms of two major epigenetic phenomena: DNA methylation and histone modification. As epigenetics involves many cellular processes, it is no surprise that it can also influence disease-associated gene expression. A direct link between respiratory infections, host cell epigenetic regulations, and chronic lung diseases is still unknown. Recent studies have revealed bacterium- or virus-induced epigenetic changes in the host cells. In this review, we focused on respiratory pathogens (viruses, bacteria, and fungi) induced epigenetic modulations (DNA methylation and histone modification) that may contribute to lung disease pathophysiology by promoting host defense or allowing pathogen persistence.
... The feasible association of these proteins having distinct DNA methyltransferases (DNMTs) were nicely studied [40]. Menachery et al. found that a feasible accumulation of global H3K27me3 with suppression of interferon-stimulated gene (ISG) expression through DNA methylation was responsible for antigen presentation after H5N1VN1203 and MERS-CoV infections [43]. Upon infection, the feasible association of H3K4me3 and TNF-α is also observed to induce the innate immune responses in monocytes, and antigen presentation of DC1 and T H 1/T H 17-mediated immune response [44,45]. ...
... IL-6 can modulate the functions and expressions of several genes by blocking DNMTs (DNMT1 and DNMT3B) [43]. The IL-6 gene is observed to be activated in DCs through acetylation of the KLF4 transcription factor in inflammation-induced ARDS [142,143]. ...
The COVID-19 outbreak has created disaster globally, and mankind is yet to come in terms with combating this global menace. Amid this turmoil, immunocompromised individuals like cancer patients exhibit dismal immune responses toward such infection. In order to treat cancer patients during such adverse situations, it is necessary to understand the phenomena that interlink these two diseased states. Modulation of host epigenetic landscape is a key hallmark of both cancer and viral infections, including COVID-19. Our review aims to shed light upon the interplay between COVID-19 and cancer, primarily through the genetic and epigenetic modulations of the gene expression profile, so as to design better therapeutic strategies in the near future.
... Doctors at the forefront of the fight against coronavirus in China are less inclined to use steroid drugs. However, the use of steroid drugs in low doses is lifesaving in some patients (61). Immunomodulatory clinical practitioners extensively employed corticosteroids during the SARS pandemic (2002)(2003), and based on the clinical feedback, they could lead to early favorable changes, such as drop-in pyrexia, resolution of radiographic lung infiltration, and oxygenation improvement (62,63). ...
The newly emerged coronavirus (SARS-CoV-2) is virulent, contagious, and has rapidly gained many mutations, which makes it highly infectious and swiftly transmissible around the world. SARS-CoV-2 infects people of all ages and targets all body organs and their cellular compartments, starting from the respiratory system, where it shows many deleterious effects, to other tissues and organs. Systemic infection can lead to severe cases that require intensive intervention. Multiple approaches were elaborated, approved, and successfully used in the intervention of the SARS-CoV-2 infection. These approaches range from the utilization of single and/or mixed medications to specialized supportive devices. For critically ill COVID-19 patients with acute respiratory distress syndrome, both extracorporeal membrane oxygenation (ECMO) and hemadsorption are utilized in combination or individually to support and release the etiological factors responsible for the “cytokine storm” underlying this condition. The current report discusses hemadsorption devices that can be used as part of supportive treatment for the COVID-19-associated cytokine storm.
... Respiratory viral infections are a common trigger of ARDS in children. Pathogenic influenza and coronaviruses use host epigenetic reprogramming to evade the host immune response (42,43). In the current analysis, histone deacetylases (HDACs) were found to be a top pathway associated moderate/severe ARDS. ...
Background:
There is no generalizable transcriptomics signature of pediatric acute respiratory distress syndrome. Our goal was to identify a whole blood differential gene expression signature for pediatric acute hypoxemic respiratory failure (AHRF) using transcriptomic microarrays within twenty-four hours of diagnosis. We used publicly available human whole-blood gene expression arrays of a Berlin-defined pediatric acute respiratory distress syndrome (GSE147902) cohort and a sepsis-triggered AHRF (GSE66099) cohort within twenty-four hours of diagnosis and compared those children with a PaO2/FiO2 < 200 to those with a PaO2/FiO2 ≥ 200.
Results:
We used stability selection, a bootstrapping method of 100 simulations using logistic regression as a classifier, to select differentially expressed genes associated with a PaO2/FiO2 < 200 vs. PaO2/FiO2 ≥ 200. The top-ranked genes that contributed to the AHRF signature were selected in each dataset. Genes common to both of the top 1,500 ranked gene lists were selected for pathway analysis. Pathway and network analysis was performed using the Pathway Network Analysis Visualizer (PANEV) and Reactome was used to perform an over-representation gene network analysis of the top-ranked genes common to both cohorts. Changes in metabolic pathways involved in energy balance, fundamental cellular processes such as protein translation, mitochondrial function, oxidative stress, immune signaling, and inflammation are differentially regulated early in pediatric ARDS and sepsis-induced AHRF compared to both healthy controls and to milder acute hypoxemia. Specifically, fundamental pathways related to the severity of hypoxemia emerged and included (1) ribosomal and eukaryotic initiation of factor 2 (eIF2) regulation of protein translation and (2) the nutrient, oxygen, and energy sensing pathway, mTOR, activated via PI3K/AKT signaling.
Conclusions:
Cellular energetics and metabolic pathways are important mechanisms to consider to further our understanding of the heterogeneity and underlying pathobiology of moderate and severe pediatric acute respiratory distress syndrome. Our findings are hypothesis generating and support the study of metabolic pathways and cellular energetics to understand heterogeneity and underlying pathobiology of moderate and severe acute hypoxemic respiratory failure in children.
... For successful infection, respiratory viruses need to overcome the host immune response through a complex combination of interactions that affect disease outcome [9] and manipulate host gene expression to ensure virus replication [17]. This is achieved in part by altering epigenetic mechanisms of the host, such as DNA methylation and histone modification. ...
... The epigenetic effector differs between viral infections. For example, it was found that DNA methylation, rather than histone modification, is crucially involved in inhibition of antigen-presentation gene expression mediated by Middle East respiratory syndrome coronavirus (MERS-CoV), whereas a combination of epigenetic mechanisms is used by H5N1-VN1203 influenza virus to target antigen presentation [9]. During infection with SARS-CoV-2, immune cells massively secrete pro-inflammatory cytokines and chemokines, leading to a cytokine storm and acute respiratory distress syndrome [4]. ...
Epigenetic modifications play a significant role in the host's immune response to viral infection. Two epigenetic events, DNA methylation and histone acetylation, are crucial for modifying the chromatin architecture and the location of regulatory elements such as promoters and enhancers. In this case-control study, we evaluated the expression of genes involved in epigenetic machinery (DNMT1, DNMT3A, DNMT3B, HDAC2, and HDAC3) and the degree of methylation of promoters of immune response genes (IFITM1/2/3, TLR3/4, TNF-α, NF-κB, and MYD88) as well as global methylation (LINE-1 and global 5–mC) in blood samples from 120 COVID-19 patients (30 mild, 30 moderate, 30 severe, and 30 critical) and 30 healthy subjects without COVID-19. In contrast to previous reports, DNMT3A and DNMT3B expression was found to be significantly downregulated in COVID-19 cases, whereas DNMT1, HDAC2, and HDAC3 expression did not change. DNMT1 and DNMT3A were negatively correlated with COVID-19 severity. Critically ill patients had lower HDAC3 expression levels. TLR4 and TNF-α had increased promoter methylation, whereas IFITM1/2/3, TLR3, NF-κB, MYD88, and LINE-1 did not differ between cases and controls. Methylation of the TNF-α promoter increased as disease severity increased. Significantly less methylation of the TLR3 promoter was observed in patients with a positive outcome (recovery). We also found a correlation between the expression of DNMT3B and the methylation level of the TLR4 promoter. In milder cases, the global 5–mC levels were lower than that in more severe cases. Our findings suggest the exclusion of DNMTs inhibitors previously recommended for COVID-19 treatment and the need for additional research in this area.
... Such patients most commonly have medical signs of nausea, dry cough, dyspnea, and two-sided imaging lung infiltration. These patients were all related to Wuhan's HUANAN SEAFOOD comprehensive market, which sells fish as well as a number of live animals, comprising chickens, snakes, birds, and marmots [69]. The contributory cause was reported from the throat gauze tests collected by the CCDC on January 7th, 20 and consequently labeled SARS-Covid-2. ...
