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1.
Int J Mol Sci ; 21(15)2020 07 23.
Article in English | MEDLINE | ID: covidwho-670369

ABSTRACT

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.


Subject(s)
Arthritis, Rheumatoid/immunology , Interleukin-6/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Arthritis, Rheumatoid/drug therapy , Disease Progression , Humans , Interleukin-6/antagonists & inhibitors , Molecular Targeted Therapy , Signal Transduction/drug effects
2.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Article in English | MEDLINE | ID: covidwho-654479

ABSTRACT

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Heat-Shock Proteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Host-Pathogen Interactions/drug effects , Pneumonia, Viral/drug therapy , Antiviral Agents/chemical synthesis , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Chromatin Assembly and Disassembly/drug effects , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation , Heat-Shock Proteins/agonists , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/agonists , Heterogeneous-Nuclear Ribonucleoproteins/antagonists & inhibitors , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Host-Pathogen Interactions/genetics , Humans , Molecular Targeted Therapy/methods , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Precursors/genetics , RNA Precursors/metabolism , Severity of Illness Index , Signal Transduction , Transcription, Genetic/drug effects , Virus Replication/drug effects
3.
Cell Rep ; 31(11): 107772, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-626232

ABSTRACT

ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-ß-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PLpro, have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15.


Subject(s)
Cytokines/metabolism , Signal Transduction , Ubiquitins/metabolism , Animals , HEK293 Cells , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Jurkat Cells , Mice , Mice, Inbred C57BL , Mycobacterium Infections/immunology , Mycobacterium Infections/metabolism , Pathogen-Associated Molecular Pattern Molecules , Typhoid Fever/immunology , Typhoid Fever/metabolism , Viral Nonstructural Proteins/metabolism
4.
In Vivo ; 34(5): 3027-3028, 2020.
Article in English | MEDLINE | ID: covidwho-740632

ABSTRACT

The FDA-approved drugs raloxifene and bazedoxifene could be among the best candidates to prevent mortality in severe COVID-19 patients. Raloxifene and bazedoxifene inhibit IL-6 signaling at therapeutic doses, suggesting they have the potential to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients, as is being shown with humanized antibodies blocking IL-6 signaling. In addition, raloxifene and bazedoxifene are selective estrogen receptor modulators with strong antiviral activity.


Subject(s)
Coronavirus Infections/drug therapy , Indoles/pharmacology , Pneumonia, Viral/drug therapy , Raloxifene Hydrochloride/pharmacology , Respiratory Distress Syndrome, Adult/drug therapy , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Receptors, Estrogen/antagonists & inhibitors , Respiratory Distress Syndrome, Adult/prevention & control , Respiratory Distress Syndrome, Adult/virology , Selective Estrogen Receptor Modulators/pharmacology , Signal Transduction/drug effects
5.
Int J Mol Sci ; 21(17)2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-740495

ABSTRACT

Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.


Subject(s)
Apoptosis/drug effects , Betacoronavirus/physiology , Cannabinoid Receptor Agonists/therapeutic use , Coronavirus Infections/drug therapy , Cytokines/immunology , Dronabinol/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome, Adult/drug therapy , Aged , Animals , Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Enterotoxins/adverse effects , Female , Humans , Lung/immunology , Lung/virology , Male , Mice , Mice, Inbred C3H , MicroRNAs/genetics , Middle Aged , Pandemics , Pneumonia/drug therapy , Pneumonia/virology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Respiratory Distress Syndrome, Adult/mortality , Respiratory Distress Syndrome, Adult/virology , Signal Transduction/drug effects
6.
Clin Sci (Lond) ; 134(16): 2137-2160, 2020 08 28.
Article in English | MEDLINE | ID: covidwho-726946

ABSTRACT

The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other ß-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Nervous System/virology , Pneumonia, Viral/virology , Signal Transduction/physiology , China , Coronavirus Infections/transmission , Humans , Pandemics , Pneumonia, Viral/transmission
7.
Aging (Albany NY) ; 12(15): 15784-15796, 2020 08 15.
Article in English | MEDLINE | ID: covidwho-721666

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an epidemic disease characterized by rapid infection and a high death toll. The clinical diagnosis of patients with COVID-19 has risen sharply, especially in Western countries. Globally, an effective treatment for COVID-19 is still limited. Vitamin A (VA) exhibits pharmacological activity in the management of pneumonia. Thus, we reason that VA may potentially serve as an anti-SARS-CoV-2 regimen. In this study, bioinformatics analysis and computation assays using a network pharmacology method were conducted to explore and uncover the therapeutic targets and mechanisms of VA for treating COVID-19. We identified candidate targets, pharmacological functions, and therapeutic pathways of VA against SARS-CoV-2. Bioinformatics findings indicate that the mechanisms of action of VA against SARS-CoV-2 include enrichment of immunoreaction, inhibition of inflammatory reaction, and biological processes related to reactive oxygen species. Furthermore, seven core targets of VA against COVID-19, including MAPK1, IL10, EGFR, ICAM1, MAPK14, CAT, and PRKCB were identified. With this bioinformatics-based report, we reveal, for the first time, the anti-SARS-CoV-2 functions and mechanisms of VA and suggest that VA may act as a potent treatment option for COVID-19, a deadly global epidemic.


Subject(s)
Betacoronavirus , Coronavirus Infections , Immunity/drug effects , Inflammation , Pandemics , Pneumonia, Viral , Vitamin A , Betacoronavirus/drug effects , Betacoronavirus/genetics , Betacoronavirus/physiology , Biological Availability , Computational Biology/methods , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Gene Ontology , Humans , Inflammation/drug therapy , Inflammation/etiology , Inflammation/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Signal Transduction/drug effects , Vitamin A/pharmacokinetics , Vitamin A/therapeutic use , Vitamins/pharmacokinetics , Vitamins/therapeutic use
8.
Science ; 369(6504): 706-712, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-717344

ABSTRACT

Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Dendritic Cells/metabolism , Interferons/physiology , Lung/metabolism , Lung/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Animals , Bronchoalveolar Lavage Fluid/immunology , Cell Proliferation , Cytokines/metabolism , Humans , Interferon Type I/metabolism , Interferons/metabolism , Lung/immunology , Mice , Mice, Inbred C57BL , Nasopharynx/immunology , Pandemics , Poly I-C/administration & dosage , Respiratory Mucosa/pathology , Signal Transduction , Staphylococcal Infections/metabolism , Superinfection , Toll-Like Receptor 3/metabolism
9.
Am J Physiol Cell Physiol ; 319(2): C244-C249, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-711625

ABSTRACT

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydrogen Sulfide/therapeutic use , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Hydrogen Sulfide/metabolism , Lung/drug effects , Lung/metabolism , Lung/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Serine Endopeptidases/metabolism , Signal Transduction
10.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-709757

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Disease Models, Animal , Interferon Type I/metabolism , Mice/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Animals , Cell Line, Tumor , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dependovirus/genetics , Female , Humans , Inflammation/metabolism , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , Pandemics , Parvoviridae Infections/metabolism , Parvoviridae Infections/virology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Signal Transduction/genetics , Virus Replication/genetics
11.
Cells ; 9(8)2020 08 11.
Article in English | MEDLINE | ID: covidwho-706247

ABSTRACT

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Betacoronavirus/drug effects , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , Drug Therapy, Combination , Humans , Inflammation/immunology , Inflammation/metabolism , Mice , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Signal Transduction/drug effects , Treatment Outcome , Virus Internalization/drug effects
12.
Int J Biol Sci ; 16(13): 2464-2476, 2020.
Article in English | MEDLINE | ID: covidwho-695855

ABSTRACT

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused infections worldwide. However, the correlation between the immune infiltration and coronavirus disease 2019 (COVID-19) susceptibility or severity in cancer patients remains to be fully elucidated. ACE2 expressions in normal tissues, cancers and cell lines were comprehensively assessed. Furthermore, we compared ACE2 expression between cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we performed gene set enrichment analysis (GSEA) to investigate the related signaling pathways. Finally, the correlations between ACE2 expression and immune infiltration were investigated via Tumor Immune Estimation Resource (TIMER) and GEPIA. We found that ACE2 was predominantly expressed in both adult and fetal tissues from the digestive, urinary and male reproductive tracts; moreover, ACE2 expressions in corresponding cancers were generally higher than that in matched healthy tissues. GSEA showed that various metabolic and immune-related pathways were significantly associated with ACE2 expression across multiple cancer types. Intriguingly, we found that ACE2 expression correlated significantly with immune cell infiltration in both normal and cancer tissues, especially in the stomach and colon. These findings proposed a possible fecal-oral and maternal-fetal transmission of SARS-CoV-2 and suggested that cancers of the respiratory, digestive or urinary tracts would be more vulnerable to SARS-CoV-2 infection.


Subject(s)
Computational Biology , Coronavirus Infections/immunology , Neoplasms/immunology , Pneumonia, Viral/immunology , Adult , Betacoronavirus , Coronavirus Infections/complications , Enterocytes/metabolism , Epithelial Cells/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Expression Regulation, Viral , Genotype , Goblet Cells/metabolism , Hepatocytes/metabolism , Humans , Immune System , Kidney Tubules/embryology , Male , Neoplasms/complications , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Prognosis , RNA-Seq , Signal Transduction
13.
Virus Res ; 287: 198108, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-694184

ABSTRACT

Viral infections are dangerous diseases for human health worldwide, which lead to significant morbidity and mortality each year. Because of their importance and the lack of effective therapeutic approaches, further attempts should be made to discover appropriate alternative or complementary treatments. Melatonin, a multifunctional neurohormone mainly synthesized and secreted by the pineal gland, plays some roles in the treatment of viral infections. Regarding a deadly outbreak of COVID-19 across the world, we decided to discuss melatonin functions against various viral infections including COVID-19. Therefore, in this review, we summarize current evidence on melatonin therapy for viral infections with focus on possible underlying mechanisms of melatonin actions.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Melatonin/pharmacology , Pneumonia, Viral/virology , Antioxidants , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Host-Pathogen Interactions , Humans , Melatonin/therapeutic use , Oxidative Stress/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Signal Transduction/drug effects , Vaccination , Viral Vaccines/administration & dosage , Viral Vaccines/immunology , Virus Diseases/drug therapy , Virus Diseases/metabolism , Virus Diseases/virology
14.
Nat Commun ; 11(1): 3810, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-690732

ABSTRACT

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-ß promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-ß treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Immune Evasion , Interferon Type I/metabolism , Pneumonia, Viral/virology , Signal Transduction , Betacoronavirus/genetics , Betacoronavirus/immunology , Betacoronavirus/metabolism , Cell Line , Coronavirus Infections/immunology , Humans , Immunity, Innate , Interferon-beta/genetics , Interferon-beta/metabolism , Interferon-beta/pharmacology , Mutation , Open Reading Frames , Pandemics , Pneumonia, Viral/immunology , Promoter Regions, Genetic , Signal Transduction/drug effects , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Replication/drug effects
15.
Front Immunol ; 11: 1625, 2020.
Article in English | MEDLINE | ID: covidwho-688729

ABSTRACT

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Pandemics , Pneumonia, Viral , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
16.
Front Immunol ; 11: 1337, 2020.
Article in English | MEDLINE | ID: covidwho-687353

ABSTRACT

Autophagy is a cellular recycling system found in almost all types of eukaryotic organisms. The system is made up of a variety of proteins which function to deliver intracellular cargo to lysosomes for formation of autophagosomes in which the contents are degraded. The maintenance of cellular homeostasis is key in the survival and function of a variety of human cell populations. The interconnection between metabolism and autophagy is extensive, therefore it has a role in a variety of different cell functions. The disruption or dysfunction of autophagy in these cell types have been implicated in the development of a variety of inflammatory diseases including asthma. The role of autophagy in non-immune and immune cells both lead to the pathogenesis of lung inflammation. Autophagy in pulmonary non-immune cells leads to tissue remodeling which can develop into chronic asthma cases with long term effects. The role autophagy in the lymphoid and myeloid lineages in the pathology of asthma differ in their functions. Impaired autophagy in lymphoid populations have been shown, in general, to decrease inflammation in both asthma and inflammatory disease models. Many lymphoid cells rely on autophagy for effector function and maintained inflammation. In stark contrast, autophagy deficient antigen presenting cells have been shown to have an activated inflammasome. This is largely characterized by a TH17 response that is accompanied with a much worse prognosis including granulocyte mediated inflammation and steroid resistance. The cell specificity associated with changes in autophagic flux complicates its targeting for amelioration of asthmatic symptoms. Differing asthmatic phenotypes between TH2 and TH17 mediated disease may require different autophagic modulations. Therefore, treatments call for a more cell specific and personalized approach when looking at chronic asthma cases. Viral-induced lung inflammation, such as that caused by SARS-CoV-2, also may involve autophagic modulation leading to inflammation mediated by lung resident cells. In this review, we will be discussing the role of autophagy in non-immune cells, myeloid cells, and lymphoid cells for their implications into lung inflammation and asthma. Finally, we will discuss autophagy's role viral pathogenesis, immunometabolism, and asthma with insights into autophagic modulators for amelioration of lung inflammation.


Subject(s)
Asthma/complications , Asthma/pathology , Autophagy/immunology , Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/pathology , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Animals , Asthma/immunology , Autophagosomes/metabolism , Autophagy/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Dendritic Cells/metabolism , Humans , Lymphocytes/metabolism , Lysosomes/metabolism , Myeloid Cells/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Respiratory Mucosa/metabolism , Signal Transduction/immunology
17.
Int J Mol Sci ; 21(15)2020 Jul 27.
Article in English | MEDLINE | ID: covidwho-680190

ABSTRACT

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pulmonary Fibrosis/prevention & control , Betacoronavirus/drug effects , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Disease Progression , Humans , Pandemics , Phosphodiesterase Inhibitors/pharmacology , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Signal Transduction/drug effects , Treatment Outcome
18.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-678269

ABSTRACT

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Angiotensin II Type 1 Receptor Blockers/classification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Bromhexine/pharmacology , Bromhexine/therapeutic use , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Clinical Trials as Topic/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Diminazene/pharmacology , Diminazene/therapeutic use , Drug Repositioning/methods , Drug Repositioning/standards , Drug Repositioning/trends , Gabexate/analogs & derivatives , Gabexate/pharmacology , Gabexate/therapeutic use , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Receptor, Angiotensin, Type 1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/therapeutic use , Signal Transduction/drug effects
19.
Int J Mol Sci ; 21(14)2020 Jul 21.
Article in English | MEDLINE | ID: covidwho-671084

ABSTRACT

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Catechin/analogs & derivatives , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Antioxidants/therapeutic use , Autoimmune Diseases/drug therapy , Betacoronavirus/drug effects , Betacoronavirus/immunology , Catechin/therapeutic use , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Humans , NF-kappa B/antagonists & inhibitors , Pandemics , Plant Extracts/therapeutic use , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/prevention & control , STAT1 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects
20.
Cells ; 9(8)2020 07 22.
Article in English | MEDLINE | ID: covidwho-669617

ABSTRACT

The ectonucleotidases CD39 and CD73 regulate immune responses by balancing extracellular ATP and adenosine in inflammation and are likely to be involved in the pathophysiology of COVID-19. Here, we analyzed CD39 and CD73 on different lymphocyte populations in a small cohort of COVID-19 patients and in healthy individuals. We describe a significantly lower level of expression of CD73 on cytotoxic lymphocyte populations, including CD8+ T, natural killer T (NKT), and natural killer (NK) cells, during COVID-19. Interestingly, the decrease of CD73 on CD8+ T cells and NKT cells correlated with serum ferritin levels. Furthermore, we observed distinct functional differences between the CD73+ and CD73- subsets of CD8+ T cells and NKT cells with regard to cytokine/toxin secretion. In COVID-19 patients, the majority of the CD73-CD8+ T cells were capable of secreting granzyme B, perforin, tumor necrosis factor (TNF-α) or interferon-gamma (IFN-γ). To conclude, in this first study of CD39 and CD73 expression of lymphocytes in COVID-19, we show that CD8+ T cells and NKT cells lacking CD73 possess a significantly higher cytotoxic effector functionality compared to their CD73+ counterparts. Future studies should investigate differences of cellular CD39 and CD73 expression in patients at different disease stages and their potential as prognostic markers or targets for immunomodulatory therapies.


Subject(s)
5'-Nucleotidase/metabolism , Apyrase/metabolism , Coronavirus Infections/immunology , Killer Cells, Natural/immunology , Natural Killer T-Cells/immunology , Pneumonia, Viral/immunology , T-Lymphocytes, Cytotoxic/immunology , Adenosine/metabolism , Adult , Aged , Betacoronavirus , Coronavirus Infections/enzymology , Female , GPI-Linked Proteins/metabolism , Granzymes/metabolism , Humans , Inflammation/enzymology , Inflammation/immunology , Interferon-gamma/metabolism , Male , Middle Aged , Pandemics , Perforin/metabolism , Pneumonia, Viral/enzymology , Signal Transduction/immunology , T-Lymphocytes, Cytotoxic/metabolism , Tumor Necrosis Factor-alpha/metabolism
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