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1.
Clin Exp Rheumatol ; 38(2): 337-342, 2020.
Article in English | MEDLINE | ID: covidwho-831030

ABSTRACT

A severe outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019, and spread so rapidly that more than 200,000 cases have so far been reported worldwide; on January 30, 2020, the WHO declared it the sixth public health emergency of international concern. The two previously reported coronavirus epidemics (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) share similar pathogenetic, epidemiological and clinical features as COVID-19. As little is currently known about SARS-CoV-2, it is likely that lessons learned from these major epidemics can be applied to the new pandemic, including the use of novel immunosuppressive drugs.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antirheumatic Agents/therapeutic use , Betacoronavirus , Coronavirus Infections , Cytokines/metabolism , Pandemics , Pneumonia, Viral , China/epidemiology , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Humans , Infection Control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology
2.
J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-823496

ABSTRACT

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Subject(s)
Axons/immunology , Axons/metabolism , CD4 Antigens/deficiency , Coronavirus Infections/immunology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Poliomyelitis/etiology , Animals , Axons/pathology , Brain/immunology , Brain/metabolism , Brain/pathology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Coronavirus Infections/pathology , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice
3.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Article in English | MEDLINE | ID: covidwho-810756

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Atazanavir Sulfate/pharmacology , Betacoronavirus/drug effects , Cytokines/metabolism , Ritonavir/pharmacology , Animals , Atazanavir Sulfate/chemistry , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Therapy, Combination , Humans , Inflammation/metabolism , Inflammation/virology , Lopinavir/pharmacology , Molecular Docking Simulation , Monocytes/virology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Protease Inhibitors/pharmacology , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
4.
Anatol J Cardiol ; 24(4): 224-234, 2020 10.
Article in English | MEDLINE | ID: covidwho-809639

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by 'Severe Acute Respiratory Syndrome Coronavirus-2' (SARS-CoV-2) infection emerged in Wuhan, a city of China, and spread to the entire planet in early 2020. The virus enters the respiratory tract cells and other tissues via ACE2 receptors. Approximately 20% of infected subjects develop severe or critical disease. A cytokine storm leads to over inflammation and thrombotic events. The most common clinical presentation in COVID-19 is pneumonia, typically characterized by bilateral, peripheral, and patchy infiltrations in the lungs. However multi-systemic involvement including peripheral thromboembolic skin lesions, central nervous, gastrointestinal, circulatory, and urinary systems are reported. The disease has a higher mortality compared to other viral agents causing pneumonia and unfortunately, no approved specific therapy, nor vaccine has yet been discovered. Several clinical trials are ongoing with hydroxychloroquine, remdesivir, favipiravir, and low molecular weight heparins. This comprehensive review aimed to summarize coagulation abnormalities reported in COVID-19, discuss the thrombosis, and inflammation-driven background of the disease, emphasize the impact of thrombotic and inflammatory processes on the progression and prognosis of COVID-19, and to provide evidence-based therapeutic guidance, especially from antithrombotic and anti-inflammatory perspectives.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Inflammation/virology , Pneumonia, Viral/complications , Thrombosis/virology , Blood Coagulation Disorders/therapy , Blood Coagulation Disorders/virology , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Coronavirus Infections/virology , Cytokines/metabolism , Hemostatic Disorders/virology , Humans , Immunomodulation/physiology , Inflammation/therapy , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , Prognosis , Thrombosis/therapy
5.
Eur Rev Med Pharmacol Sci ; 24(17): 9169-9171, 2020 09.
Article in English | MEDLINE | ID: covidwho-790178

ABSTRACT

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.


Subject(s)
Cardiovascular Diseases/prevention & control , Coronavirus Infections/diagnosis , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia, Viral/diagnosis , Betacoronavirus/isolation & purification , Clinical Trials as Topic , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Inflammasomes/metabolism , Myocarditis/prevention & control , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Nitriles/therapeutic use , Pandemics , Pneumonia, Viral/virology , Prognosis , Venous Thromboembolism/prevention & control , ortho-Aminobenzoates/therapeutic use
8.
Front Immunol ; 11: 2069, 2020.
Article in English | MEDLINE | ID: covidwho-769216

ABSTRACT

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Galectin 3/antagonists & inhibitors , Galectin 3/blood , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Pulmonary Fibrosis/drug therapy , Severity of Illness Index , Animals , Betacoronavirus/chemistry , Biomarkers/blood , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Disease Progression , Host-Pathogen Interactions/immunology , Humans , Inflammation/drug therapy , Inflammation/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prognosis , Pulmonary Fibrosis/immunology , Spike Glycoprotein, Coronavirus/metabolism
9.
EBioMedicine ; 58: 102887, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-684307

ABSTRACT

The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/etiology , Cytokines/metabolism , Pneumonia, Viral/etiology , Renin-Angiotensin System , Animals , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Feedback, Physiological , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology
10.
Biomed Res Int ; 2020: 1594726, 2020.
Article in English | MEDLINE | ID: covidwho-633800

ABSTRACT

Acute kidney injury (AKI) is a common complication of sepsis and has also been observed in some patients suffering from the new coronavirus pneumonia COVID-19, which is currently a major global concern. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has a variety of beneficial properties including anti-inflammatory and antioxidative activities. Here, we investigated the possible protective effects of TQ against kidney damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ+CLP. CLP was performed after 2 weeks of TQ gavage. After 48 h, we measured the histopathological alterations in the kidney tissue and the serum levels of creatinine (CRE) and blood urea nitrogen (BUN). We also evaluated pyroptosis (NLRP3, caspase-1), apoptosis (caspase-3, caspase-8), proinflammatory (TNF-α, IL-1ß, and IL-6)-related protein and gene expression levels. Our results demonstrated that TQ inhibited CLP-induced increased serum CRE and BUN levels. It also significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1ß, and IL-6 induced by CLP. Furthermore, NF-κB protein level was significantly decreased in the TQ+CLP group than in the CLP group. Together, our results indicate that TQ may be a potential therapeutic agent for sepsis-induced AKI.


Subject(s)
Acute Kidney Injury/drug therapy , Acute Kidney Injury/etiology , Benzoquinones/therapeutic use , Sepsis/complications , Sepsis/drug therapy , Acute Kidney Injury/pathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/therapeutic use , Apoptosis/drug effects , Betacoronavirus , Blood Urea Nitrogen , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Creatinine/blood , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
11.
Viruses ; 12(6)2020 06 24.
Article in English | MEDLINE | ID: covidwho-620517

ABSTRACT

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Subject(s)
Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/virology , Respiratory Mucosa/cytology , Respiratory Mucosa/virology , Animals , Bronchi/cytology , Bronchi/virology , Cells, Cultured , Chemokines/metabolism , Cytokines/metabolism , Dogs , Host-Pathogen Interactions , Humans , Immunity, Innate , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/epidemiology , Intercellular Junctions , Madin Darby Canine Kidney Cells , Models, Biological , Mucin 5AC/metabolism , Pandemics , Virus Cultivation
12.
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
15.
Phytomedicine ; 78: 153296, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-747894

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections , Glucosides/pharmacology , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral , Animals , Chlorocebus aethiops , Coronavirus/drug effects , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , Forsythia/chemistry , Humans , Phytotherapy , Plant Extracts/pharmacology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Severe Acute Respiratory Syndrome/virology , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
16.
Eur Rev Med Pharmacol Sci ; 24(16): 8585-8591, 2020 08.
Article in English | MEDLINE | ID: covidwho-745634

ABSTRACT

Some surface proteins of the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can bind to the hemoglobin molecule of an erythrocyte, which leads to the destruction of the structure of the heme and the release of harmful iron ions to the bloodstream. The degradation of hemoglobin results in the impairment of oxygen-carrying capacity of the blood, and the accumulation of free iron enhances the production of reactive oxygen species. Both events can lead to the development of oxidative stress. In this case, oxidative damage to the lungs leads then to the injuries of all other tissues and organs. The use of uridine, which preserves the structure of pulmonary alveoli and the air-blood barrier of the lungs in the course of experimental severe hypoxia, and dihydroquercetin, an effective free radical scavenger, is promising for the treatment of COVID-19. These drugs can also be used for the recovery of the body after the severe disease.


Subject(s)
Coronavirus Infections/pathology , Oxidative Stress , Pneumonia, Viral/pathology , Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokines/metabolism , Erythrocytes/cytology , Erythrocytes/metabolism , Erythrocytes/virology , Free Radical Scavengers/pharmacology , Free Radical Scavengers/therapeutic use , Hemoglobins/metabolism , Humans , Oxidative Stress/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/physiology , Quercetin/analogs & derivatives , Quercetin/pharmacology , Quercetin/therapeutic use , Reactive Oxygen Species/metabolism , Uridine/pharmacology , Uridine/therapeutic use
17.
Eur Rev Med Pharmacol Sci ; 24(16): 8606-8620, 2020 08.
Article in English | MEDLINE | ID: covidwho-745632

ABSTRACT

OBJECTIVE: COVID-19 immune syndrome is a multi-systemic disorder induced by the COVID-19 infection. Pathobiological transitions and clinical stages of the COVID-19 syndrome following the attack of SARS-CoV-2 on the human body have not been fully explored. The aim of this review is to outline the three critical prominent phase regarding the clinicogenomics course of the COVID-19 immune syndrome. MATERIALS AND METHODS: In the clinical setting, the COVID-19 process presents as "asymptomatic/pre-symptomatic phase", "respiratory phase with mild/moderate/severe symptoms" and "multi-systemic clinical syndrome with impaired/disproportionate and/or defective immunity". The corresponding three genomic phases include the "ACE2, ANPEP transcripts in the initial phase", "EGFR and IGF2R transcripts in the propagating phase" and the "immune system related critical gene involvements of the complicating phase". RESULTS: The separation of the phases is important since the genomic features of each phase are different from each other and these different mechanisms lead to distinct clinical multi-systemic features. Comprehensive genomic profiling with next generation sequencing may play an important role in defining and clarifying these three unique separate phases for COVID-19. From our point of view, it is important to understand these unique phases of the syndrome in order to approach a COVID-19 patient bedside. CONCLUSIONS: This three-phase approach may be useful for future studies which will focus on the clinical management and development of the vaccines and/or specific drugs targeting the COVID-19 processes. ANPEP gene pathway may have a potential for the vaccine development. Regarding the specific disease treatments, MAS agonists, TXA127, Angiotensin (1-7) and soluble ACE2 could have therapeutic potential for the COVID-19 course. Moreover, future CRISPR technology can be utilized for the genomic editing and future management of the clinical course of the syndrome.


Subject(s)
Asymptomatic Diseases , Coronavirus Infections/pathology , Immune System/metabolism , Pneumonia, Viral/pathology , Betacoronavirus/isolation & purification , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation , Humans , Multiple Organ Failure/etiology , Multiple Organ Failure/pathology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Prognosis , Receptor, IGF Type 2/genetics , Receptor, IGF Type 2/metabolism , Sepsis/complications , Sepsis/pathology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
18.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-744478

ABSTRACT

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/immunology , Mucosal-Associated Invariant T Cells/metabolism , Natural Killer T-Cells/metabolism , Phenotype , Pneumonia, Viral/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Respiratory Distress Syndrome, Adult/immunology , Aged , Antigens, CD/blood , Antigens, Differentiation, T-Lymphocyte/blood , Cells, Cultured , Coronavirus Infections/virology , Cytokines/metabolism , Female , Humans , Inflammation/immunology , Inflammation/metabolism , Lectins, C-Type/blood , Male , Middle Aged , Mucosal-Associated Invariant T Cells/immunology , Natural Killer T-Cells/immunology , Pandemics , Pneumonia, Viral/virology , Prognosis , Prospective Studies , Respiratory Distress Syndrome, Adult/virology , Severity of Illness Index
19.
Eur Heart J ; 41(32): 3038-3044, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-741847

ABSTRACT

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Endothelium, Vascular/physiopathology , Oxidative Stress , Pneumonia, Viral/complications , Thrombosis/etiology , Coronavirus Infections/epidemiology , Cytokines/metabolism , Humans , Pandemics , Pneumonia, Viral/epidemiology , Thrombosis/metabolism , Thrombosis/physiopathology
20.
EBioMedicine ; 59: 102964, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-733877

ABSTRACT

Mononuclear phagocytes are a widely distributed family of cells contributing to innate and adaptive immunity. Circulating monocytes and tissue macrophages participate in all stages of SARS COVID-19. They contribute to comorbidities predisposing to clinical infection, virus resistance and dissemination, and to host factors that determine disease severity, recovery and sequelae. Assays are available to detect viral infection and antibody responses, but no adequate tests have been developed to measure the activation level of monocytes and tissue macrophages, and the risk of progression to a fatal hyperinflammatory syndrome. Blood monocytes provide a window on the systemic immune response, from production to tissue recruitment, reflecting the impact of infection on the host. Ready availability of blood makes it possible to monitor severity and the risk of potentially lethal complications, by developing tests to assess the status of monocyte activation and its potential for further inflammatory dysregulation after recruitment to tissues and during recovery.


Subject(s)
Coronavirus Infections/pathology , Monocytes/immunology , Pneumonia, Viral/pathology , Betacoronavirus/isolation & purification , Comorbidity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Immunity, Innate , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Monocytes/cytology , Monocytes/metabolism , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Severity of Illness Index
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