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1.
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
2.
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
4.
Pathol Res Pract ; 216(9): 153086, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-649184

ABSTRACT

A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin-angiotensin-aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/etiology , Coronavirus Infections/virology , Lung/virology , Pneumonia, Viral/virology , Cardiovascular Diseases/metabolism , Cardiovascular System/virology , Coronavirus Infections/complications , Humans , Lung/metabolism , Pandemics , Pneumonia, Viral/complications , Renin-Angiotensin System/physiology
5.
Am J Physiol Lung Cell Mol Physiol ; 319(3): L408-L415, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-646985

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene. Although viral respiratory tract infections are, in general, more severe in patients with CF compared with the general population, a small number of studies indicate that SARS-CoV-2 does not cause a worse infection in CF. This is surprising since comorbidities including preexisting lung disease have been reported to be associated with worse outcomes in SARS-CoV-2 infections. Several recent studies provide insight into why SARS-CoV-2 may not produce more severe outcomes in CF. First, ACE and ACE2, genes that play key roles in SARS-CoV-2 infection, have some variants that are predicted to reduce the severity of SARS-CoV-2 infection. Second, mRNA for ACE2 is elevated and mRNA for TMPRSS2, a serine protease, is decreased in CF airway epithelial cells. Increased ACE2 is predicted to enhance SARS-CoV-2 binding to cells but would increase conversion of angiotensin II, which is proinflammatory, to angiotensin-1-7, which is anti-inflammatory. Thus, increased ACE2 would reduce inflammation and lung damage due to SARS-CoV-2. Moreover, decreased TMPRSS2 would reduce SARS-CoV-2 entry into airway epithelial cells. Second, many CF patients are treated with azithromycin, which suppresses viral infection and lung inflammation and inhibits the activity of furin, a serine protease. Finally, the CF lung contains high levels of serine protease inhibitors including ecotin and SERPINB1, which are predicted to reduce the ability of TMPRSS2 to facilitate SARS-CoV-2 entry into airway epithelial cells. Thus, a variety of factors may mitigate the severity of SARS-CoV-2 in CF.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/etiology , Cystic Fibrosis/virology , Inflammation/virology , Pneumonia, Viral/etiology , Cystic Fibrosis/metabolism , Epithelial Cells/virology , Humans , Inflammation/metabolism , Lung/metabolism , Lung/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism
6.
Genes (Basel) ; 11(7)2020 07 07.
Article in English | MEDLINE | ID: covidwho-640013

ABSTRACT

The global spread of COVID-19, caused by pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for an imminent response from medical research communities to better understand this rapidly spreading infection. Employing multiple bioinformatics and computational pipelines on transcriptome data from primary normal human bronchial epithelial cells (NHBE) during SARS-CoV-2 infection revealed activation of several mechanistic networks, including those involved in immunoglobulin G (IgG) and interferon lambda (IFNL) in host cells. Induction of acute inflammatory response and activation of tumor necrosis factor (TNF) was prominent in SARS-CoV-2 infected NHBE cells. Additionally, disease and functional analysis employing ingenuity pathway analysis (IPA) revealed activation of functional categories related to cell death, while those associated with viral infection and replication were suppressed. Several interferon (IFN) responsive gene targets (IRF9, IFIT1, IFIT2, IFIT3, IFITM1, MX1, OAS2, OAS3, IFI44 and IFI44L) were highly upregulated in SARS-CoV-2 infected NBHE cell, implying activation of antiviral IFN innate response. Gene ontology and functional annotation of differently expressed genes in patient lung tissues with COVID-19 revealed activation of antiviral response as the hallmark. Mechanistic network analysis in IPA identified 14 common activated, and 9 common suppressed networks in patient tissue, as well as in the NHBE cell model, suggesting a plausible role for these upstream regulator networks in the pathogenesis of COVID-19. Our data revealed expression of several viral proteins in vitro and in patient-derived tissue, while several host-derived long noncoding RNAs (lncRNAs) were identified. Our data highlights activation of IFN response as the main hallmark associated with SARS-CoV-2 infection in vitro and in human, and identified several differentially expressed lncRNAs during the course of infection, which could serve as disease biomarkers, while their precise role in the host response to SARS-CoV-2 remains to be investigated.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , RNA, Long Noncoding/metabolism , Viral Proteins/metabolism , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Biomarkers/metabolism , Bronchi/cytology , Cell Death , Cell Line , Cluster Analysis , Coronavirus Infections/genetics , Coronavirus Infections/virology , Epithelial Cells/cytology , Epithelial Cells/virology , Gene Regulatory Networks , Humans , Immunity, Innate , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , Lung/metabolism , Lung/pathology , Lung/virology , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , RNA, Long Noncoding/genetics , Transcriptome
7.
Cardiovasc Res ; 116(10): 1733-1741, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-637912

ABSTRACT

AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. METHODS AND RESULTS: With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0-5%, I2 = 0%] in non-ICU patients to 59% (95% CI 48-71%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. CONCLUSION: Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Myocardium/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/metabolism , Humans , Lung/metabolism , Lung/virology , Pandemics , Peptide Hydrolases/metabolism , Proteolysis
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(10): 165889, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-627951

ABSTRACT

The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19.


Subject(s)
Central Nervous System Diseases/pathology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , Central Nervous System Diseases/complications , Central Nervous System Diseases/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Humans , Lung/metabolism , Lung/virology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Viral Envelope Proteins/antagonists & inhibitors , Viral Envelope Proteins/metabolism , Viral Fusion Proteins/antagonists & inhibitors , Viral Fusion Proteins/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
10.
Front Cell Infect Microbiol ; 10: 327, 2020.
Article in English | MEDLINE | ID: covidwho-615468

ABSTRACT

COVID-19 morbidity and mortality have significant gender disparities, with higher prevalence and mortality in men. SARS-CoV-2 enters the lungs through the ACE2 enzyme, a member of the renin-angiotensin system (RAS). Although there are no data for the lung, the expressions of RAS components in other tissues are modulated by sex hormones, androgens, and estrogens. However, there are no data on sex-specific differences in ACE2 expression. If there is a sex difference in the expression of ACE2 in the lung, this could theoretically explain the gender disparity in COVID-19 disease. More importantly, although modulation of ACE2 will certainly not provide a cure for the COVID-19 disease, modulation of ACE2 by sex hormone modulators, if they affect the expression of ACE2, could potentially be developed into a supportive therapy for COVID-19 patients.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Androgens/blood , Betacoronavirus , Coronavirus Infections/pathology , Estrogens/blood , Female , Humans , Lung/metabolism , Male , Pandemics , Pneumonia, Viral/pathology , Sex Distribution , Sex Factors
11.
Med Arch ; 74(2): 134-138, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-613836

ABSTRACT

Introduction: COVID-19 is a new viral illness that can affect the lungs and airways with lethal consequences leading to the death of the patients. The ACE2 receptors were widely disturbed among body tissues such as lung, kidney, small intestine, heart, and others in different percent and considered a target for the nCOVID-19 virus. S-protein of the virus was binding to ACE2 receptors caused downregulation of endogenous anti-viral mediators, upregulation of NF-κB pathway, ROS and pro-apoptotic protein. Nrf2 was a transcription factor that's play a role in generation of anti-oxidant enzymes. Aim: To describe and establish role of Nrf2 activators for treatment COVID-19 positive patients. Methods: We used method of analysis of the published papers with described studies about COVID-19 connected with pharmacological issues and aspects which are included in global fighting against COVID-19 infection, and how using DMF (Nrf2 activator) in clinical trial for nCOVID-19 produce positive effects in patients for reduce lung alveolar cells damage. Results: we are found that Nrf2 activators an important medication that's have a role in reduce viral pathogenesis via inhibit virus entry through induce SPLI gene expression as well as inhibit TRMPSS2, upregulation of ACE2 that's make a competition with the virus on binding site, induce gene expression of anti-viral mediators such as RIG-1 and INFs, induce anti-oxidant enzymes, also they have a role in inhibit NF-κB pathway, inhibit both apoptosis proteins and gene expression of TLRs. Conclusion: We are concluded that use DMF (Nrf2 activator) in clinical trial for nCOVID-19 positive patients to reduce lung alveolar cells damage.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Lung/metabolism , NF-E2-Related Factor 2/metabolism , Pneumonia, Viral/metabolism , Alveolar Epithelial Cells/metabolism , Humans , Pandemics , Pulmonary Alveoli/metabolism
12.
Front Immunol ; 11: 1130, 2020.
Article in English | MEDLINE | ID: covidwho-612409

ABSTRACT

The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.


Subject(s)
Coronavirus Infections/immunology , Immunotherapy , Iron Metabolism Disorders/immunology , Pneumonia, Viral/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Cytokines/immunology , Ferritins/blood , Fever , Humans , Inflammation , Lung/metabolism , Lung/physiopathology , Pandemics , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Syndrome
13.
J Exp Med ; 217(8)2020 08 03.
Article in English | MEDLINE | ID: covidwho-607919

ABSTRACT

The renin-angiotensin system (RAS) has long been appreciated as a major regulator of blood pressure, but has more recently been recognized as a mechanism for modulating inflammation as well. While there has been concern in COVID-19 patients over the use of drugs that target this system, the RAS has not been explored fully as a druggable target. The abbreviated description of the RAS suggests that its dysregulation may be at the center of COVID-19.


Subject(s)
Coronavirus Infections/physiopathology , Lung Diseases/physiopathology , Lung/virology , Pneumonia, Viral/physiopathology , Angiotensin I/metabolism , Animals , Blood Coagulation Disorders/virology , Coronavirus Infections/etiology , Coronavirus Infections/metabolism , Cytokines/metabolism , Humans , Hypertension/physiopathology , Lung/metabolism , Lung/physiopathology , Lung Diseases/metabolism , Lung Diseases/virology , Obesity/physiopathology , Pandemics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Receptor, Angiotensin, Type 1/metabolism , Severity of Illness Index
14.
Ther Adv Respir Dis ; 14: 1753466620933508, 2020.
Article in English | MEDLINE | ID: covidwho-602119

ABSTRACT

The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Coronavirus Infections/immunology , Cytokines/immunology , Immunity, Innate , Lung/metabolism , Pneumonia, Viral/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism
16.
Cell ; 182(3): 744-753.e4, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-592074

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/therapy , Disease Models, Animal , Pneumonia, Viral/therapy , Animals , Chlorocebus aethiops , Coronavirus Infections/virology , Female , HEK293 Cells , Humans , Immunization, Passive/methods , Lung/metabolism , Lung/virology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Transduction, Genetic , Vero Cells , Viral Load/immunology
17.
CPT Pharmacometrics Syst Pharmacol ; 9(8): 435-443, 2020 08.
Article in English | MEDLINE | ID: covidwho-574626

ABSTRACT

Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC90 ) for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The final model described the data reported in eight publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first dose and for ~ 14 days following 500 mg q.d. for 3 days or 500 mg q.d. for 1 day/250 mg q.d. on days 2-5, 10 days following a single 1,000 mg dose, and for > 20 days with 500 mg q.d. for 10 days. AM concentrations exceeded the 90% inhibitory concentration for > 20 days for all regimens. These data will better inform optimization of dosing regimens for AZ clinical trials.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Azithromycin/administration & dosage , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Anti-Bacterial Agents/pharmacokinetics , Azithromycin/pharmacokinetics , Dose-Response Relationship, Drug , Humans , Leukocytes, Mononuclear/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Models, Biological , Neutrophils/metabolism , Pandemics , Tissue Distribution
18.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L115-L120, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-558506

ABSTRACT

COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.


Subject(s)
Alveolar Epithelial Cells/virology , Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Epithelial Cells/virology , Pneumonia, Viral/virology , Alveolar Epithelial Cells/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/virology , Humans , Lung/metabolism , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology
19.
Acta Diabetol ; 57(7): 779-783, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-549301

ABSTRACT

AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Lung/metabolism , Pneumonia, Viral/drug therapy , Coronavirus Infections/enzymology , Dipeptidyl Peptidase 4/drug effects , Humans , Pandemics , Pneumonia, Viral/enzymology
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