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2.
Cells ; 11(4)2022 02 13.
Article in English | MEDLINE | ID: covidwho-1686622

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19's inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease.


Subject(s)
COVID-19/metabolism , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/metabolism , Adaptive Immunity/immunology , Amino Acid Transport Systems, Neutral/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/physiology , COVID-19/immunology , COVID-19/transmission , Humans , Immunity, Innate/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation/immunology , Kynurenine/metabolism , Receptors, Aryl Hydrocarbon/physiology , SARS-CoV-2/pathogenicity , Signal Transduction , Tryptophan/metabolism
3.
Biol Direct ; 16(1): 18, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1477451

ABSTRACT

Skeletal muscle has an extraordinary regenerative capacity reflecting the rapid activation and effective differentiation of muscle stem cells (MuSCs). In the course of muscle regeneration, MuSCs are reprogrammed by immune cells. In turn, MuSCs confer immune cells anti-inflammatory properties to resolve inflammation and facilitate tissue repair. Indeed, MuSCs can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory ability, including effects primed by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). At the molecular level, the tryptophan metabolites, kynurenine or kynurenic acid, produced by indoleamine 2,3-dioxygenase (IDO), augment the expression of TNF-stimulated gene 6 (TSG6) through the activation of the aryl hydrocarbon receptor (AHR). In addition, insulin growth factor 2 (IGF2) produced by MuSCs can endow maturing macrophages oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functions. Herein, we summarize the current understanding of the immunomodulatory characteristics of MuSCs and the issues related to their potential applications in pathological conditions, including COVID-19.


Subject(s)
COVID-19/therapy , Immune System/physiology , Muscles/physiology , Regeneration/physiology , Stem Cells/cytology , Animals , COVID-19/immunology , Cell Adhesion Molecules/metabolism , Cell Differentiation , Cell Proliferation , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation , Insulin-Like Growth Factor II/metabolism , Interferon-gamma/metabolism , Kynurenic Acid/metabolism , Kynurenine/metabolism , Macrophages/metabolism , Mice , Muscles/metabolism , Oxidative Phosphorylation , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/chemistry , Tumor Necrosis Factor-alpha/metabolism
4.
Front Immunol ; 12: 624293, 2021.
Article in English | MEDLINE | ID: covidwho-1394756

ABSTRACT

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which interacts with a wide range of organic molecules of endogenous and exogenous origin, including environmental pollutants, tryptophan metabolites, and microbial metabolites. The activation of AHR by these agonists drives its translocation into the nucleus where it controls the expression of a large number of target genes that include the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines. Recent advances reveal that AHR signaling modulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. This review will focus on the increasing evidence supporting a role for AHR as a modulator of the host response to viral infection.


Subject(s)
Adaptive Immunity , Immunity, Innate , Receptors, Aryl Hydrocarbon/metabolism , Virus Diseases/virology , Viruses/immunology , Active Transport, Cell Nucleus , Animals , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Ligands , Signal Transduction , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/metabolism , Viruses/genetics , Viruses/pathogenicity
7.
Nat Commun ; 12(1): 5148, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1376197

ABSTRACT

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.


Subject(s)
Coronavirus Infections/metabolism , Coronavirus/physiology , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/virology , Epithelial Cells/metabolism , Epithelial Cells/virology , Female , Humans , Male , Receptors, Aryl Hydrocarbon/genetics , SARS-CoV-2/physiology
8.
Sci Rep ; 11(1): 16629, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361646

ABSTRACT

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/agonists , COVID-19/drug therapy , Carbazoles/pharmacology , Omeprazole/pharmacology , Receptors, Aryl Hydrocarbon/agonists , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/virology , Carbazoles/therapeutic use , Chlorocebus aethiops , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Hep G2 Cells , Humans , Omeprazole/therapeutic use , RNA-Seq , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Vero Cells , Virus Internalization/drug effects
9.
Int J Mol Sci ; 22(14)2021 Jul 18.
Article in English | MEDLINE | ID: covidwho-1314669

ABSTRACT

A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Cigarette Smoking/adverse effects , SARS-CoV-2/drug effects , Smoking/adverse effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Cigarette Smoking/physiopathology , Disease Susceptibility , Epithelial Cells/metabolism , Epithelial Cells/virology , Gingiva/metabolism , Gingiva/virology , Humans , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Virus/metabolism , Respiratory Mucosa/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Smoking/metabolism
10.
Biochem Pharmacol ; 188: 114564, 2021 06.
Article in English | MEDLINE | ID: covidwho-1188321

ABSTRACT

The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-α mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , Anthocyanins/pharmacology , Drug Discovery/methods , Gene Expression Regulation, Enzymologic , Receptors, Aryl Hydrocarbon/agonists , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Animals , Anthocyanins/chemistry , Chlorocebus aethiops , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Protein Structure, Secondary , Protein Structure, Tertiary , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/metabolism , Vero Cells
12.
Chem Biol Interact ; 338: 109428, 2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1103757

ABSTRACT

Camostat mesylate, a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2), is currently under investigation for its effectiveness in COVID-19 patients. For its safe application, the risks of camostat mesylate to induce pharmacokinetic drug-drug interactions with co-administered drugs should be known. We therefore tested in vitro the potential inhibition of important efflux (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2)), and uptake transporters (organic anion transporting polypeptides OATP1B1, OATP1B3, OATP2B1) by camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). Transporter inhibition was evaluated using fluorescent probe substrates in transporter over-expressing cell lines and compared to the respective parental cell lines. Moreover, possible mRNA induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) was analysed in LS180 cells by quantitative real-time PCR. The results of our study for the first time demonstrated that camostat mesylate and GBPA do not relevantly inhibit P-gp, BCRP, OATP1B1 or OATP1B3. Only OATP2B1 was profoundly inhibited by GBPA with an IC50 of 11 µM. Induction experiments in LS180 cells excluded induction of PXR-regulated genes such as cytochrome P450 3A4 (CYP3A4) and ABCB1 and AhR-regulated genes such as CYP1A1 and CYP1A2 by camostat mesylate and GBPA. Together with the summary of product characteristics of camostat mesylate indicating no inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, our data suggest a low potential of camostat mesylate to act as a perpetrator in pharmacokinetic drug-drug interactions. Only inhibition of OATP2B1 by GBPA warrants further investigation.


Subject(s)
Drug Interactions , Esters/metabolism , Guanidines/metabolism , Serine Proteinase Inhibitors/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Cell Line , Cell Survival/drug effects , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Esters/chemistry , Esters/pharmacology , Guanidines/chemistry , Guanidines/pharmacology , Humans , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/metabolism , Pregnane X Receptor/genetics , Pregnane X Receptor/metabolism , RNA, Messenger/metabolism , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology
13.
Int J Mol Sci ; 22(4)2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1069827

ABSTRACT

The metabolism of tryptophan is intimately associated with the differential regulation of diverse physiological processes, including in the regulation of responses to severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection that underpins the COVID-19 pandemic. Two important products of tryptophan metabolism, viz kynurenine and interleukin (IL)4-inducible1 (IL41)-driven indole 3 pyruvate (I3P), activate the aryl hydrocarbon receptor (AhR), thereby altering the nature of immune responses to SARS-CoV-2 infection. AhR activation dysregulates the initial pro-inflammatory cytokines production driven by neutrophils, macrophages, and mast cells, whilst AhR activation suppresses the endogenous antiviral responses of natural killer cells and CD8+ T cells. Such immune responses become further dysregulated by the increased and prolonged pro-inflammatory cytokine suppression of pineal melatonin production coupled to increased gut dysbiosis and gut permeability. The suppression of pineal melatonin and gut microbiome-derived butyrate, coupled to an increase in circulating lipopolysaccharide (LPS) further dysregulates the immune response. The AhR mediates its effects via alterations in the regulation of mitochondrial function in immune cells. The increased risk of severe/fatal SARS-CoV-2 infection by high risk conditions, such as elderly age, obesity, and diabetes are mediated by these conditions having expression levels of melatonin, AhR, butyrate, and LPS that are closer to those driven by SARS-CoV-2 infection. This has a number of future research and treatment implications, including the utilization of melatonin and nutraceuticals that inhibit the AhR, including the polyphenols, epigallocatechin gallate (EGCG), and resveratrol.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/physiology , Tryptophan/metabolism , Animals , COVID-19/complications , COVID-19/physiopathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/physiopathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/physiopathology
14.
Int J Mol Sci ; 22(1)2020 Dec 25.
Article in English | MEDLINE | ID: covidwho-1004733

ABSTRACT

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3ß, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven 'backward' conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3ß by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.


Subject(s)
Neoplasms/pathology , Tumor Microenvironment , Acetyl Coenzyme A/metabolism , Age Factors , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Computational Biology , Humans , Immunomodulation , Melatonin/metabolism , Metabolic Networks and Pathways , Mitochondria/metabolism , Models, Biological , Neoplasms/etiology , Neoplasms/metabolism , Organ Specificity/genetics , Organ Specificity/immunology , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Sirtuins/metabolism , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
15.
Biosci Rep ; 40(10)2020 10 30.
Article in English | MEDLINE | ID: covidwho-989979

ABSTRACT

COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is overexpressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and adenosine triphosphate (ATP), especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide (NAM), which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 (silent mating type information regulation 2 homologue 1) inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines and is effective against HIV infection. These properties qualify NAM for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.


Subject(s)
Coronavirus Infections/drug therapy , Niacinamide/pharmacology , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Betacoronavirus/drug effects , COVID-19 , Cell Line , Coronavirus Infections/pathology , Cytokines/blood , Humans , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/metabolism , Pandemics , Pneumonia, Viral/pathology , Poly (ADP-Ribose) Polymerase-1/metabolism , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2
16.
Cell Res ; 30(12): 1078-1087, 2020 12.
Article in English | MEDLINE | ID: covidwho-912896

ABSTRACT

Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-ß or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.


Subject(s)
Interferons/metabolism , Mucus/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Animals , COVID-19/pathology , COVID-19/virology , Cell Line , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Hypoxia , Interferon-beta/pharmacology , Interferon-gamma/pharmacology , Lung/metabolism , Lung/pathology , Macaca , Mice , Mice, Inbred ICR , Mice, Transgenic , Mucins/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Signal Transduction , Up-Regulation/drug effects
17.
Environ Toxicol Pharmacol ; 81: 103520, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-885274

ABSTRACT

Many diverse strategies allow and facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral innate immune mechanisms. Although the type I interferon (IFN) system has a critical role in restricting the dissemination of viral infection, suppression of IFN receptor signals by SARS-CoV-2 constitutes a checkpoint that plays an important role in the immune escape of the virus. Environmental pollution not only facilitates SARS-CoV-2 infection but also increases infection-associated fatality risk, which arises due to Systemic Aryl hydrocarbon Receptor (AhR) Activation Syndrome. The intracellular accumulation of endogenous kynurenic acid due to overexpression of the indoleamine 2,3-dioxygenase (IDO) by AhR activation induces AhR-interleukin-6 (IL-6)-signal transducers and activators of the transcription 3 (STAT3) signaling pathway. The AhR-IDO1-Kynurenine pathway is an important checkpoint, which leads to fatal consequences in SARS-CoV-2 infection and immune evasion in the context of Treg/Th17 imbalance and cytokine storm.


Subject(s)
COVID-19/immunology , Environmental Pollution/adverse effects , Immune Evasion/immunology , Immunity, Innate/immunology , Inflammation Mediators/immunology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Humans , Immune Evasion/drug effects , Immunity, Innate/drug effects , Inflammation Mediators/metabolism , Receptors, Aryl Hydrocarbon/immunology , Receptors, Aryl Hydrocarbon/metabolism
18.
Food Chem Toxicol ; 141: 111418, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-345861

ABSTRACT

Occupational, residential, dietary and environmental exposures to mixtures of synthetic anthropogenic chemicals after World War II have a strong relationship with the increase of chronic diseases, health cost and environmental pollution. The link between environment and immunity is particularly intriguing as it is known that chemicals and drugs can cause immunotoxicity (e.g., allergies and autoimmune diseases). In this review, we emphasize the relationship between long-term exposure to xenobiotic mixtures and immune deficiency inherent to chronic diseases and epidemics/pandemics. We also address the immunotoxicologic risk of vulnerable groups, taking into account biochemical and biophysical properties of SARS-CoV-2 and its immunopathological implications. We particularly underline the common mechanisms by which xenobiotics and SARS-CoV-2 act at the cellular and molecular level. We discuss how long-term exposure to thousand chemicals in mixtures, mostly fossil fuel derivatives, exposure toparticle matters, metals, ultraviolet (UV)-B radiation, ionizing radiation and lifestyle contribute to immunodeficiency observed in the contemporary pandemic, such as COVID-19, and thus threaten global public health, human prosperity and achievements, and global economy. Finally, we propose metrics which are needed to address the diverse health effects of anthropogenic COVID-19 crisis at present and those required to prevent similar future pandemics.


Subject(s)
Air Pollutants/toxicity , Betacoronavirus , Coronavirus Infections/epidemiology , Pesticides/toxicity , Pneumonia, Viral/epidemiology , Xenobiotics/toxicity , Animals , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/physiopathology , Diet , Epidemics , Humans , Immune System/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/physiopathology , Prevalence , Receptors, Aryl Hydrocarbon/metabolism , Risk Factors , SARS-CoV-2 , Signal Transduction/drug effects , Time
19.
J Virol ; 94(3)2020 01 17.
Article in English | MEDLINE | ID: covidwho-124739

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor/transcription factor that modulates several cellular and immunological processes following activation by pathogen-associated stimuli, though its role during virus infection is largely unknown. Here, we show that AhR is activated in cells infected with mouse hepatitis virus (MHV), a coronavirus (CoV), and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) during infection. Knockdown of TiPARP reduced viral replication and increased interferon expression, suggesting that TiPARP functions in a proviral manner during MHV infection. We also show that MHV replication induced the expression of other genes known to be downstream of AhR in macrophages and dendritic cells and in livers of infected mice. Further, we found that chemically inhibiting or activating AhR reciprocally modulated the expression levels of cytokines induced by infection, specifically, interleukin 1ß (IL-1ß), IL-10, and tumor necrosis factor alpha (TNF-α), consistent with a role for AhR activation in the host response to MHV infection. Furthermore, while indoleamine 2,3-dioxygenase (IDO1) drives AhR activation in other settings, MHV infection induced equal expression of downstream genes in wild-type (WT) and IDO1-/- macrophages, suggesting an alternative pathway of AhR activation. In summary, we show that coronaviruses elicit AhR activation by an IDO1-independent pathway, contributing to upregulation of downstream effectors, including the proviral factor TiPARP, and to modulation of cytokine gene expression, and we identify a previously unappreciated role for AhR signaling in CoV pathogenesis.IMPORTANCE Coronaviruses are a family of positive-sense RNA viruses with human and agricultural significance. Characterizing the mechanisms by which coronavirus infection dictates pathogenesis or counters the host immune response would provide targets for the development of therapeutics. Here, we show that the aryl hydrocarbon receptor (AhR) is activated in cells infected with a prototypic coronavirus, mouse hepatitis virus (MHV), resulting in the expression of several effector genes. AhR is important for modulation of the host immune response to MHV and plays a role in the expression of TiPARP, which we show is required for maximal viral replication. Taken together, our findings highlight a previously unidentified role for AhR in regulating coronavirus replication and the immune response to the virus.


Subject(s)
Cytokines/metabolism , Gene Expression Regulation, Enzymologic , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Murine hepatitis virus/physiology , Poly(ADP-ribose) Polymerases/biosynthesis , Proviruses/physiology , Receptors, Aryl Hydrocarbon/metabolism , Virus Replication/physiology , Animals , Cytokines/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Mice , Mice, Knockout , Poly(ADP-ribose) Polymerases/genetics , Receptors, Aryl Hydrocarbon/genetics , Signal Transduction
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