Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
1.
Cell Mol Life Sci ; 79(2): 94, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1653404

ABSTRACT

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.


Subject(s)
Autoimmune Diseases/pathology , Citrullination/physiology , Inflammation/pathology , Protein Processing, Post-Translational/physiology , Protein-Arginine Deiminases/metabolism , COVID-19/pathology , Citrulline/biosynthesis , Energy Metabolism/physiology , Extracellular Traps/immunology , Gene Expression Regulation/genetics , Humans , Neoplasms/pathology , SARS-CoV-2/immunology , Thromboembolism/pathology
2.
Thromb Haemost ; 122(1): 113-122, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1324456

ABSTRACT

OBJECTIVES: Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. METHODS: We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex- and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EVs) and citrullinated histone H3 levels were determined in plasma upon inclusion by flow cytometry and immunoassay. RESULTS: In total, 20 patients had severe and 21 nonsevere disease. The number of EV (median [25th, 75th percentile]) was significantly higher in patients compared with controls (658.8 [353.2, 876.6] vs. 435.5 [332.5, 585.3], geometric mean ratio [95% confidence intervals]: 2.6 [1.9, 3.6]; p < 0.001). Patients exhibited significantly higher numbers of EVs derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EVs from alveolar-macrophages and alveolar-epithelial cells were detectable in plasma and were significantly higher in patients. Intercellular adhesion molecule-1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin-converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and nonsevere COVID-19. Citrullinated histone H3 levels (ng/mL, median [25th, 75th percentile]) were higher in patients than in controls (1.42 [0.6, 3.4] vs. 0.31 [0.1, 0.6], geometric mean ratio: 4.44 [2.6, 7.7]; p < 0.001), and were significantly lower in patients with nonsevere disease compared with those with severe disease. CONCLUSION: EV and citrullinated histone H3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.


Subject(s)
COVID-19/blood , Extracellular Vesicles/pathology , Histones/blood , SARS-CoV-2 , Adult , Aged , Biomarkers/blood , Blood Platelets/pathology , COVID-19/complications , Case-Control Studies , Citrullination , Extracellular Traps/metabolism , Female , Histones/chemistry , Humans , Male , Middle Aged , Pandemics , Severity of Illness Index , /etiology
3.
Cell Death Differ ; 28(11): 3125-3139, 2021 11.
Article in English | MEDLINE | ID: covidwho-1241944

ABSTRACT

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.


Subject(s)
COVID-19/pathology , Extracellular Traps/metabolism , Neutrophils/immunology , COVID-19/complications , COVID-19/immunology , Citrullination , Complement Activation , Humans , Neutrophils/metabolism , Platelet Activation , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombosis/etiology
4.
Genome ; 64(4): 372-385, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1006430

ABSTRACT

The COVID-19 pandemic is one of the most significant public health threats in recent history and has impacted the lives of almost everyone worldwide. Epigenetic mechanisms contribute to many aspects of the SARS-CoV-2 replication cycle, including expression levels of viral receptor ACE2, expression of cytokine genes as part of the host immune response, and the implication of various histone modifications in several aspects of COVID-19. SARS-CoV-2 proteins physically associate with many different host proteins over the course of infection, and notably there are several interactions between viral proteins and epigenetic enzymes such as HDACs and bromodomain-containing proteins as shown by correlation-based studies. The many contributions of epigenetic mechanisms to the viral life cycle and the host immune response to infection have resulted in epigenetic factors being identified as emerging biomarkers for COVID-19, and project epigenetic modifiers as promising therapeutic targets to combat COVID-19. This review article highlights the major epigenetic pathways at play during COVID-19 disease and discusses ongoing clinical trials that will hopefully contribute to slowing the spread of SARS-CoV-2.


Subject(s)
COVID-19/genetics , COVID-19/virology , Epigenesis, Genetic , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/genetics , Citrullination , Cytokines/genetics , DNA Methylation , Histones/chemistry , Humans , Pandemics
5.
JCI Insight ; 5(11)2020 06 04.
Article in English | MEDLINE | ID: covidwho-980226

ABSTRACT

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis - including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.


Subject(s)
Cell-Free Nucleic Acids/metabolism , Coronavirus Infections/metabolism , Extracellular Traps/metabolism , Histones/metabolism , Neutrophils/metabolism , Peroxidase/metabolism , Pneumonia, Viral/metabolism , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19 , Case-Control Studies , Citrullination , Coronavirus Infections/blood , Coronavirus Infections/therapy , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Lymphocyte Count , Male , Middle Aged , Pandemics , Platelet Count , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Respiration, Artificial , Severity of Illness Index
SELECTION OF CITATIONS
SEARCH DETAIL