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2.
Mol Syst Biol ; 16(7): e9628, 2020 07.
Article in English | MEDLINE | ID: covidwho-707164

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , A549 Cells , Betacoronavirus , Bleomycin/pharmacology , Dexamethasone/pharmacology , Drug Design , Drug Evaluation, Preclinical , Erlotinib Hydrochloride/pharmacology , Fluphenazine/pharmacology , HEK293 Cells , Humans , Kidney/drug effects , Lung/drug effects , MCF-7 Cells , Pandemics , Peptidyl-Dipeptidase A , Systems Biology , Up-Regulation , Vemurafenib/pharmacology
3.
Int J Environ Res Public Health ; 17(15)2020 08 02.
Article in English | MEDLINE | ID: covidwho-693532

ABSTRACT

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists -coping with the high inter-individual variability of COVID-19, and for policy makers -coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM)2.5 concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February-31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM2.5 levels and the incidence (r = 0.67, p < 0.0001), the mortality rate (r = 0.65, p < 0.0001) and the case fatality rate (r = 0.7, p < 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.


Subject(s)
Air Pollution/adverse effects , Coronavirus Infections/virology , Particulate Matter/adverse effects , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Base Sequence , Betacoronavirus , Coronavirus Infections/epidemiology , Humans , Italy/epidemiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Promoter Regions, Genetic , Receptors, Virus/genetics , Up-Regulation
4.
Int J Mol Sci ; 21(15)2020 Jul 31.
Article in English | MEDLINE | ID: covidwho-693525

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 virus, overlaps with the ongoing epidemics of cigarette smoking and electronic cigarette (e-cig) vaping. However, there is scarce data relating COVID-19 risks and outcome with cigarette or e-cig use. In this study, we mined three independent RNA expression datasets from smokers and vapers to understand the potential relationship between vaping/smoking and the dysregulation of key genes and pathways related to COVID-19. We found that smoking, but not vaping, upregulates ACE2, the cellular receptor that SARS-CoV-2 requires for infection. Both smoking and use of nicotine and flavor-containing e-cigs led to upregulation of pro-inflammatory cytokines and inflammasome-related genes. Specifically, chemokines including CCL20 and CXCL8 are upregulated in smokers, and CCL5 and CCR1 are upregulated in flavor/nicotine-containing e-cig users. We also found genes implicated in inflammasomes, such as CXCL1, CXCL2, NOD2, and ASC, to be upregulated in smokers and these e-cig users. Vaping flavor and nicotine-less e-cigs, however, did not lead to significant cytokine dysregulation and inflammasome activation. Release of inflammasome products, such as IL-1B, and cytokine storms are hallmarks of COVID-19 infection, especially in severe cases. Therefore, our findings demonstrated that smoking or vaping may critically exacerbate COVID-19-related inflammation or increase susceptibility to COVID-19.


Subject(s)
Electronic Nicotine Delivery Systems , Immune System/metabolism , Peptidyl-Dipeptidase A/metabolism , Tobacco Smoking , Adult , Betacoronavirus/isolation & purification , Bronchi/cytology , Chemokine CCL20/genetics , Chemokine CCL20/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Humans , Interleukin-1beta/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Middle Aged , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/metabolism , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Up-Regulation , Young Adult
6.
Front Immunol ; 11: 1472, 2020.
Article in English | MEDLINE | ID: covidwho-643141

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).


Subject(s)
Angiotensin II/blood , Betacoronavirus/metabolism , Coronavirus Infections/blood , Coronavirus Infections/physiopathology , Pneumonia, Viral/blood , Pneumonia, Viral/physiopathology , Up-Regulation , Age Factors , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Brain/immunology , Brain/metabolism , Cellular Senescence/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Critical Illness , Cytokines/metabolism , Dopamine/metabolism , Down-Regulation , Humans , Immunotherapy/methods , Mitochondria/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Prognosis , Renin-Angiotensin System/immunology
7.
mBio ; 11(3)2020 06 23.
Article in English | MEDLINE | ID: covidwho-612678

ABSTRACT

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.


Subject(s)
Betacoronavirus/immunology , CD47 Antigen/metabolism , Immunomodulation/immunology , Receptors, Pattern Recognition/immunology , A549 Cells , Adaptive Immunity/immunology , Animals , CD47 Antigen/genetics , Cell Line, Tumor , Cytokines/immunology , Female , Humans , Immunity, Innate/immunology , Lymphocytic choriomeningitis virus/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/immunology , Up-Regulation/immunology
9.
Front Immunol ; 11: 1372, 2020.
Article in English | MEDLINE | ID: covidwho-619471

ABSTRACT

Current guidelines for COVID-19 management recommend the utilization of various repurposed drugs. Despite ongoing research toward the development of a vaccine against SARS-CoV-2, such a vaccine will not be available in time to contribute to the containment of the ongoing pandemic. Therefore, there is an urgent need to develop a framework for the rapid identification of novel targets for diagnostic and therapeutic interventions. We analyzed publicly available transcriptomic datasets of SARS-CoV infected humans and mammals to identify consistent differentially expressed genes then validated in SARS-CoV-2 infected epithelial cells transcriptomic datasets. Comprehensive toxicogenomic analysis of the identified genes to identify possible interactions with clinically proven drugs was carried out. We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. These findings indicate that analysis of publicly available transcriptomic and toxicogenomic data represents a rapid approach for the identification of novel targets and molecules that can modify the action of such targets during the early phases of emerging infections like COVID-19.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Gene Expression Profiling , Membrane Proteins/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , RNA-Binding Proteins/genetics , 2',5'-Oligoadenylate Synthetase/genetics , Animals , Antiviral Agents/pharmacology , Betacoronavirus/physiology , Disease Models, Animal , Ferrets , Gene Expression Regulation/drug effects , Humans , Immunity, Innate , Lung , Macaca fascicularis , Mice , Myxovirus Resistance Proteins/genetics , Pandemics , Species Specificity , Up-Regulation/drug effects , Valproic Acid/pharmacology
10.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-436643

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Brain Ischemia/virology , Brain/blood supply , Diabetes Mellitus , Peptidyl-Dipeptidase A/biosynthesis , Receptors, Virus/biosynthesis , Smokers , Stroke/virology , Up-Regulation , Animals , Betacoronavirus/pathogenicity , Brain/drug effects , Brain Ischemia/genetics , Brain Ischemia/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Models, Animal , Disease Susceptibility , Infarction, Middle Cerebral Artery/complications , Male , Mice , Mice, Inbred C57BL , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Rats , Rats, Sprague-Dawley , Receptors, Virus/genetics , Smoke/adverse effects , Stroke/genetics , Stroke/metabolism , Up-Regulation/drug effects
11.
Int J Mol Sci ; 21(10)2020 May 21.
Article in English | MEDLINE | ID: covidwho-327277

ABSTRACT

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Subject(s)
Androgens/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Serine Endopeptidases/genetics , Smoking/metabolism , Up-Regulation , Alveolar Epithelial Cells/metabolism , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Humans , Mouth Mucosa/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Smoking/epidemiology , Smoking/genetics
12.
J Thorac Oncol ; 15(7): e101-e103, 2020 07.
Article in English | MEDLINE | ID: covidwho-291629

ABSTRACT

The coronavirus disease 2019 outbreak is evolving rapidly worldwide. The lungs are the target of the primary infection and patients with lung cancer seem to have a poor prognosis. To our knowledge, this is the first reported investigation of a possible role of interleukin-17 target therapy in patients with lung cancer and concomitant severe acute respiratory syndrome-coronavirus-2 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections , Interleukin-17 , Lung Neoplasms , Pandemics , Pneumonia, Viral , Respiratory Distress Syndrome, Adult , Betacoronavirus/drug effects , Betacoronavirus/physiology , Chemokines, CXC/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Drug Discovery , Humans , Inflammation/immunology , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Respiratory Distress Syndrome, Adult/drug therapy , Respiratory Distress Syndrome, Adult/immunology , Th17 Cells/immunology , Up-Regulation/drug effects
13.
Dev Cell ; 53(5): 514-529.e3, 2020 06 08.
Article in English | MEDLINE | ID: covidwho-276241

ABSTRACT

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.


Subject(s)
Alveolar Epithelial Cells/metabolism , Coronavirus Infections/epidemiology , Interferons/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Respiratory Mucosa/metabolism , Tobacco Smoke Pollution/adverse effects , Tobacco Smoking/genetics , Adult , Aged , Animals , Caco-2 Cells , Cells, Cultured , Female , HCT116 Cells , Humans , Interferons/genetics , Male , Mice , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Seq , Rats , Signal Transduction , Single-Cell Analysis , Tobacco Smoking/epidemiology , Tobacco Smoking/metabolism , Up-Regulation
14.
Thromb Res ; 192: 23-26, 2020 08.
Article in English | MEDLINE | ID: covidwho-245642

ABSTRACT

AIM: An increased risk of venous thromboembolism (VTE) in patients with COVID-19 pneumonia admitted to intensive care unit (ICU) has been reported. Whether COVID-19 increases the risk of VTE in non-ICU wards remains unknown. We aimed to evaluate the burden of asymptomatic deep vein thrombosis (DVT) in COVID-19 patients with elevated D-dimer levels. METHOD: In this prospective study consecutive patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia and D-dimer > 1000 ng/ml were screened for asymptomatic DVT with complete compression doppler ultrasound (CCUS). The study was approved by the Institutional Ethics Committee. RESULTS: The study comprised 156 patients (65.4% male). All but three patients received standard doses of thromboprophylaxis. Median days of hospitalization until CCUS was 9 (IQR 5-17). CCUS was positive for DVT in 23 patients (14.7%), of whom only one was proximal DVT. Seven patients (4.5%) had bilateral distal DVT. Patients with DVT had higher median D-dimer levels: 4527 (IQR 1925-9144) ng/ml vs 2050 (IQR 1428-3235) ng/ml; p < 0.001. D-dimer levels > 1570 ng/ml were associated with asymptomatic DVT (OR 9.1; CI 95% 1.1-70.1). D-dimer showed an acceptable discriminative capacity (area under the ROC curve 0.72, 95% CI 0.61-0.84). CONCLUSION: In patients admitted with COVID-19 pneumonia and elevated D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series. Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Fibrin Fibrinogen Degradation Products/analysis , Pneumonia, Viral/epidemiology , Venous Thrombosis/epidemiology , Anticoagulants/administration & dosage , Asymptomatic Diseases , Biomarkers/blood , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Female , Humans , Incidence , Male , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Predictive Value of Tests , Prospective Studies , Risk Assessment , Risk Factors , Spain/epidemiology , Time Factors , Treatment Outcome , Up-Regulation , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/prevention & control , Venous Thrombosis/virology
15.
J Pharm Pharm Sci ; 23(1): 75-85, 2020.
Article in English | MEDLINE | ID: covidwho-196744

ABSTRACT

The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.


Subject(s)
Coronavirus Infections/drug therapy , Estrogens/therapeutic use , Pneumonia, Viral/drug therapy , Receptors, Estrogen/physiology , Adaptive Immunity , Age Factors , Animals , Betacoronavirus , Comorbidity , Coronavirus Infections/mortality , Estrogens, Conjugated (USP)/therapeutic use , Female , Humans , Immunity, Innate , Inflammation/drug therapy , Male , Mice , Pandemics , Pneumonia, Viral/mortality , Sex Factors , Signal Transduction , Up-Regulation/drug effects
16.
J Thorac Oncol ; 15(7): e101-e103, 2020 07.
Article in English | MEDLINE | ID: covidwho-125454

ABSTRACT

The coronavirus disease 2019 outbreak is evolving rapidly worldwide. The lungs are the target of the primary infection and patients with lung cancer seem to have a poor prognosis. To our knowledge, this is the first reported investigation of a possible role of interleukin-17 target therapy in patients with lung cancer and concomitant severe acute respiratory syndrome-coronavirus-2 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections , Interleukin-17 , Lung Neoplasms , Pandemics , Pneumonia, Viral , Respiratory Distress Syndrome, Adult , Betacoronavirus/drug effects , Betacoronavirus/physiology , Chemokines, CXC/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Drug Discovery , Humans , Inflammation/immunology , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Respiratory Distress Syndrome, Adult/drug therapy , Respiratory Distress Syndrome, Adult/immunology , Th17 Cells/immunology , Up-Regulation/drug effects
19.
J Headache Pain ; 21(1): 38, 2020 Apr 25.
Article in English | MEDLINE | ID: covidwho-116495

ABSTRACT

The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.


Subject(s)
Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Coronavirus Infections/pathology , Headache/drug therapy , Ibuprofen/adverse effects , Pneumonia, Viral/pathology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus , Humans , Ibuprofen/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , Risk Factors , Up-Regulation/drug effects
20.
Cell ; 181(5): 1016-1035.e19, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-100497

ABSTRACT

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.


Subject(s)
Alveolar Epithelial Cells/metabolism , Enterocytes/metabolism , Goblet Cells/metabolism , Interferon Type I/metabolism , Nasal Mucosa/cytology , Peptidyl-Dipeptidase A/genetics , Adolescent , Alveolar Epithelial Cells/immunology , Animals , Betacoronavirus/physiology , Cell Line , Cells, Cultured , Child , Coronavirus Infections/virology , Enterocytes/immunology , Goblet Cells/immunology , HIV Infections/immunology , Humans , Influenza, Human/immunology , Interferon Type I/immunology , Lung/cytology , Lung/pathology , Macaca mulatta , Mice , Mycobacterium tuberculosis , Nasal Mucosa/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis , Tuberculosis/immunology , Up-Regulation
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