Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
1.
J Virol ; 96(5): e0208621, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1736026

ABSTRACT

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6), and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, zinc finger protein 36 (ZFP36), and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV), human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. IMPORTANCE Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.


Subject(s)
Coronavirus Infections/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Tristetraprolin/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Adenine/metabolism , Animals , Cell Line , Chlorocebus aethiops , Coronavirus Infections/genetics , Gene Expression Regulation , Humans , Infectious bronchitis virus/metabolism , Infectious bronchitis virus/pathogenicity , Interleukin-6/genetics , Interleukin-8/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Phosphorylation , Transcriptional Activation , Up-Regulation , Uridine/metabolism , Vero Cells
2.
Genes (Basel) ; 12(11)2021 10 21.
Article in English | MEDLINE | ID: covidwho-1533883

ABSTRACT

Interferon-induced transmembrane protein 3 (IFITM3), a crucial effector of the host's innate immune system, prohibits an extensive range of viruses. Previous studies have reported that single nucleotide polymorphisms (SNPs) of the IFITM3 gene are associated with the expression level and length of the IFITM3 protein and can impact susceptibility to infectious viruses and the severity of infection with these viruses. However, there have been no studies on polymorphisms of the bovine IFITM3 gene. In the present study, we finely mapped the bovine IFITM3 gene and annotated the identified polymorphisms. We investigated polymorphisms of the bovine IFITM3 gene in 108 Hanwoo and 113 Holstein cattle using direct sequencing and analyzed genotype, allele, and haplotype frequencies and linkage disequilibrium (LD) between the IFITM3 genes of the two cattle breeds. In addition, we analyzed transcription factor-binding sites and transcriptional capacity using PROMO and luciferase assays, respectively. Furthermore, we analyzed the effect of a nonsynonymous SNP of the IFITM3 gene using PolyPhen-2, PANTHER, and PROVEAN. We identified 23 polymorphisms in the bovine IFITM3 gene and found significantly different genotype, allele, and haplotype frequency distributions and LD scores between polymorphisms of the bovine IFITM3 gene in Hanwoo and Holstein cattle. In addition, the ability to bind the transcription factor Nkx2-1 and transcriptional capacities were significantly different depending on the c.-193T > C allele. Furthermore, nonsynonymous SNP (F121L) was predicted to be benign. To the best of our knowledge, this is the first genetic study of bovine IFITM3 polymorphisms.


Subject(s)
Cattle/genetics , Membrane Proteins/genetics , Regulatory Sequences, Nucleic Acid/genetics , Animals , Cells, Cultured , Gene Expression Regulation , Gene Frequency , Genotype , Haplotypes , Interferons/metabolism , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Species Specificity , Thyroid Nuclear Factor 1/physiology , Transcriptional Activation/genetics
3.
Front Immunol ; 12: 727861, 2021.
Article in English | MEDLINE | ID: covidwho-1477822

ABSTRACT

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.


Subject(s)
Gene Expression Regulation/genetics , Inflammation Mediators/metabolism , Inflammation/immunology , Ribonucleases/immunology , SARS-CoV-2/immunology , Transcription Factors/immunology , Animals , Apoptosis/genetics , COVID-19/immunology , Humans , Inflammation/pathology , Mice , NF-kappa B/metabolism , RNA Processing, Post-Transcriptional/genetics , Transcriptional Activation/immunology , Ubiquitination
4.
Molecules ; 25(21)2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-1389462

ABSTRACT

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Plant Extracts/therapeutic use , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Air Sacs/drug effects , Air Sacs/virology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19 , Chromatography, High Pressure Liquid/methods , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Disease Models, Animal , Fever/drug therapy , Fever/etiology , Hemorrhage/prevention & control , Humans , Interleukin-6/metabolism , Kidney/drug effects , Necrosis/pathology , Necrosis/prevention & control , Pandemics , Phytotherapy , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiratory Mucosa/transplantation , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/metabolism , Zebrafish
5.
Viruses ; 13(2)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1298428

ABSTRACT

The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions.


Subject(s)
Interferons/immunology , NF-kappa B/metabolism , Ubiquitination , Ubiquitins/immunology , Virus Diseases/immunology , Animals , Humans , Protein Binding , Signal Transduction/immunology , Structure-Activity Relationship , Transcriptional Activation/immunology , Virus Diseases/virology
6.
Commun Biol ; 4(1): 654, 2021 06 02.
Article in English | MEDLINE | ID: covidwho-1253994

ABSTRACT

SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , Interferons/pharmacology , Janus Kinase Inhibitors/pharmacology , Transcriptional Activation/drug effects , COVID-19/genetics , Cell Line , Humans , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Transcriptome/drug effects
7.
Mol Immunol ; 135: 268-275, 2021 07.
Article in English | MEDLINE | ID: covidwho-1211073

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have triggered global pandemic that continue to impact adversely human health. New understanding has emerged about the innate and adaptive immune responses elicited in SARS-CoV-2 infection. The understanding of innate immune responses generated in hosts early in SARS-CoV-2 infection is vital for treatment efforts. Antiviral cytokines are released by innate immune cells in response to viral infections that play a pivotal role in limiting viral replication, pathology and generating optimal adaptive immune responses alongside the long-term memory responses against reinfections. One aspect of innate immune response generated against SARS-CoV-2 in vivo and which has received much attention has been high proinflammatory cytokine release in COVID-19 patients. Another vital discovery has been that the antiviral cytokine type I Interferon (IFN) family IFN-α mediates upregulation of angiotensin converting enzyme 2 (ACE2) membrane protein in airway epithelial cells. ACE2 is a receptor that SARS-CoV-2 binds to infect host cells. New understanding has emerged about the mechanism of SARS-CoV-2 induced exaggerated proinflammatory cytokine release as well as transcriptional regulation of ACE2. This review discusses various mechanisms underlying SARS-CoV-2 induced exaggerated proinflammatory cytokine response as well as transcriptional regulation of ACE2 receptor. We further elaborate on adaptive and memory responses generated against SARS-CoV-2.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Immunity, Innate , Immunologic Memory , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , COVID-19/pathology , Humans , Transcriptional Activation/immunology
8.
Sci Rep ; 11(1): 6811, 2021 03 24.
Article in English | MEDLINE | ID: covidwho-1149746

ABSTRACT

High rate of cardiovascular disease (CVD) has been reported among patients with coronavirus disease 2019 (COVID-19). Importantly, CVD, as one of the comorbidities, could also increase the risks of the severity of COVID-19. Here we identified phospholipase A2 group VII (PLA2G7), a well-studied CVD biomarker, as a hub gene in COVID-19 though an integrated hypothesis-free genomic analysis on nasal swabs (n = 486) from patients with COVID-19. PLA2G7 was further found to be predominantly expressed by proinflammatory macrophages in lungs emerging with progression of COVID-19. In the validation stage, RNA level of PLA2G7 was identified in nasal swabs from both COVID-19 and pneumonia patients, other than health individuals. The positive rate of PLA2G7 were correlated with not only viral loads but also severity of pneumonia in non-COVID-19 patients. Serum protein levels of PLA2G7 were found to be elevated and beyond the normal limit in COVID-19 patients, especially among those re-positive patients. We identified and validated PLA2G7, a biomarker for CVD, was abnormally enhanced in COVID-19 at both nucleotide and protein aspects. These findings provided indications into the prevalence of cardiovascular involvements seen in patients with COVID-19. PLA2G7 could be a potential prognostic and therapeutic target in COVID-19.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , COVID-19/metabolism , Cardiovascular Diseases/metabolism , Macrophages/metabolism , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics , Biomarkers/metabolism , COVID-19/epidemiology , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/virology , China/epidemiology , Data Mining/methods , Humans , Macrophages/immunology , Macrophages/pathology , Polymorphism, Single Nucleotide , SARS-CoV-2/isolation & purification , Transcriptional Activation , Up-Regulation
9.
PLoS Pathog ; 16(12): e1009128, 2020 12.
Article in English | MEDLINE | ID: covidwho-992722

ABSTRACT

Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.


Subject(s)
COVID-19/immunology , Interleukin-6/immunology , Receptors, Angiotensin/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/metabolism , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Interleukin-6/metabolism , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2/metabolism , Signal Transduction/physiology , Transcriptional Activation
12.
Respir Res ; 21(1): 182, 2020 Jul 14.
Article in English | MEDLINE | ID: covidwho-647112

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects > 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. METHODS: The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. RESULTS: We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2, TGFB1, CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. CONCLUSIONS: Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.


Subject(s)
Coronavirus Infections/genetics , Gene Expression Regulation , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pulmonary Fibrosis/genetics , Respiratory Distress Syndrome/genetics , SARS Virus/genetics , Angiotensin-Converting Enzyme 2 , COVID-19 , China , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Disease Progression , Epithelial Cells/cytology , Epithelial Cells/metabolism , Female , Humans , Male , Pandemics/statistics & numerical data , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Prevalence , Pulmonary Fibrosis/epidemiology , Pulmonary Fibrosis/etiology , Receptors, Virus/metabolism , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/epidemiology , Risk Assessment , Survival Analysis , Transcription, Genetic , Transcriptional Activation/genetics
SELECTION OF CITATIONS
SEARCH DETAIL