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1.
Front Immunol ; 13: 705379, 2022.
Article in English | MEDLINE | ID: covidwho-1779938

ABSTRACT

Objectives: Recent studies suggest that asthma may have a protective effect on COVID-19.We aimed to investigate the causality between asthma and two COVID-19 outcomes and explore the mechanisms underlining this connection. Methods: Summary results of GWAS were used for the analyses, including asthma (88,486 cases and 447,859 controls), COVID-19 hospitalization (6,406 hospitalized COVID-19 cases and 902,088 controls), and COVID-19 infection (14,134 COVID-19 cases and 1,284,876 controls). The Mendelian randomization (MR) analysis was performed to evaluate the causal effects of asthma on the two COVID-19 outcomes. A cross-trait meta-analysis was conducted to analyze genetic variants within two loci shared by COVID-19 hospitalization and asthma. Results: Asthma is associated with decreased risk both for COVID-19 hospitalization (odds ratio (OR): 0.70, 95% confidence interval (CI): 0.70-0.99) and for COVID-19 infection (OR: 0.83, 95%CI: 0.51-0.95). Asthma and COVID-19 share two genome-wide significant genes, including ABO at the 9q34.2 region and OAS2 at the 12q24.13 region. The meta-analysis revealed that ABO and ATXN2 contain variants with pleiotropic effects on both COVID-19 and asthma. Conclusion: In conclusion, our results suggest that genetic liability to asthma is associated with decreased susceptibility to SARS-CoV-2 and to severe COVID-19 disease, which may be due to the protective effects of ongoing inflammation and, possibly, related compensatory responses against COVID-19 in its early stage.


Subject(s)
Asthma , COVID-19 , Asthma/epidemiology , Asthma/genetics , COVID-19/genetics , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , SARS-CoV-2
2.
Respir Res ; 22(1): 200, 2021 Jul 07.
Article in English | MEDLINE | ID: covidwho-1450712

ABSTRACT

BACKGROUND: The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics. METHODS: Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays. RESULTS: As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. CONCLUSION: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , Asthma/drug therapy , Receptors, Virus/metabolism , Respiratory Mucosa/drug effects , Administration, Inhalation , Adrenal Cortex Hormones/adverse effects , Adult , Angiotensin-Converting Enzyme 2/genetics , Asthma/diagnosis , Asthma/enzymology , Asthma/genetics , COVID-19/enzymology , COVID-19/virology , Case-Control Studies , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Receptors, Virus/genetics , Respiratory Mucosa/enzymology , SARS-CoV-2/pathogenicity , Time Factors , Up-Regulation , Virus Internalization , Young Adult
3.
Genes (Basel) ; 12(7)2021 07 09.
Article in English | MEDLINE | ID: covidwho-1302193

ABSTRACT

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Asthma/diagnosis , COVID-19 Testing , COVID-19/enzymology , Hypertension, Pulmonary/diagnosis , Lung/enzymology , Pulmonary Disease, Chronic Obstructive/diagnosis , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Asthma/enzymology , Asthma/genetics , COVID-19/genetics , Humans , Hypertension, Pulmonary/enzymology , Hypertension, Pulmonary/genetics , Inflammation/diagnosis , Inflammation/enzymology , Inflammation/genetics , Lung/pathology , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/genetics , Renin-Angiotensin System
4.
Viruses ; 13(6)2021 06 05.
Article in English | MEDLINE | ID: covidwho-1259626

ABSTRACT

Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate, and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location, and disease endotype. We found sexual dimorphism in the expression of SARS-CoV-2-related genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2, and TMPRSS4, were highly upregulated in both sexes. Overall, changes in SARS-CoV-2-related gene expression were specific to the Th2 high molecular endotype of asthma and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors wascorrelated with loss of club and ciliated cells in Th2 high asthma. Meanwhile, the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) was associated with increased goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype, and changes in epithelial heterogeneity as potential factors underlying asthmatic susceptibility, or lack thereof, to SARS-CoV-2.


Subject(s)
Asthma/immunology , COVID-19/immunology , Coronavirus Infections/immunology , Epithelial Cells/virology , Gene Expression , Host Microbial Interactions , Influenza, Human/immunology , Severity of Illness Index , Asthma/genetics , Asthma/virology , COVID-19/genetics , Coronavirus 229E, Human/genetics , Coronavirus 229E, Human/immunology , Coronavirus Infections/genetics , Epithelial Cells/classification , Female , Gene Expression Profiling , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Influenza, Human/genetics , Male , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/immunology , Orthomyxoviridae/genetics , Orthomyxoviridae/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sex Characteristics
5.
Int J Mol Sci ; 22(9)2021 May 07.
Article in English | MEDLINE | ID: covidwho-1231495

ABSTRACT

Extracellular vesicles (EVs) are membranous structures, which are secreted by almost every cell type analyzed so far. In addition to their importance for cell-cell communication under physiological conditions, EVs are also released during pathogenesis and mechanistically contribute to this process. Here we summarize their functional relevance in asthma, one of the most common chronic non-communicable diseases. Asthma is a complex persistent inflammatory disorder of the airways characterized by reversible airflow obstruction and, from a long-term perspective, airway remodeling. Overall, mechanistic studies summarized here indicate the importance of different subtypes of EVs and their variable cargoes in the functioning of the pathways underlying asthma, and show some interesting potential for the development of future therapeutic interventions. Association studies in turn demonstrate a good diagnostic potential of EVs in asthma.


Subject(s)
Asthma/metabolism , Extracellular Vesicles/metabolism , Animals , Asthma/genetics , Asthma/microbiology , Asthma/physiopathology , Biomarkers/metabolism , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Models, Biological
6.
Ann Allergy Asthma Immunol ; 127(3): 312-317, 2021 09.
Article in English | MEDLINE | ID: covidwho-1220652

ABSTRACT

OBJECTIVE: To present an update of birth cohort study designs and their contributions to allergic risk. DATA SOURCES: The PubMed database was used to search for relevant articles. STUDY SELECTIONS: Peer-reviewed prospective and retrospective studies involving the assessment of allergy using human birth cohorts between 2014 and 2021 were evaluated. RESULTS: Parental history of allergic diseases, especially in cases involving both parents, is associated with increased risk of allergy. Exposure to prenatal and postnatal smoking and limited diet diversity were associated with increased allergic burden. The impact of early-life infections and antibiotics on disease development may be associated with the onset of asthma, though this remains debated. Cohort studies also revealed that the mode of delivery and breastfeeding duration affect the odds ratio of asthma and eczema development. Household exposures, including pets, house dust mites, and scented aeroallergens may confer protective effects, whereas high air pollution exposure and low socioeconomic status may be risk enhancing. Exposure to antibiotics during early life may be associated with increased asthma risk, whereas viral infections may lead to disease protection, though the impact of the coronavirus disease 2019 pandemic on allergic risk is yet to be understood. CONCLUSION: Although evaluating the risk of allergic disease development is complex, clinicians can apply these insights on the multifactorial nature of atopy to better understand and potentially mitigate disease development.


Subject(s)
Asthma/immunology , Breast Feeding/methods , Diet/methods , Eczema/immunology , Hypersensitivity/immunology , Inheritance Patterns/immunology , Allergens/administration & dosage , Animals , Anti-Bacterial Agents/adverse effects , Asthma/etiology , Asthma/genetics , Asthma/prevention & control , Cohort Studies , Eczema/etiology , Eczema/genetics , Eczema/prevention & control , Environmental Exposure/adverse effects , Environmental Pollutants/adverse effects , Female , Humans , Hypersensitivity/etiology , Hypersensitivity/genetics , Hypersensitivity/prevention & control , Pets/immunology , Pregnancy , Pyroglyphidae/chemistry , Pyroglyphidae/immunology , Risk Factors , Virus Diseases/immunology , Virus Diseases/virology
7.
Genome Med ; 13(1): 66, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1197350

ABSTRACT

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Subject(s)
Bronchi , COVID-19/genetics , Respiratory Mucosa , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Asthma/genetics , COVID-19/immunology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Gene Expression , Genetic Variation , Humans , Middle Aged , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/genetics , Quantitative Trait Loci , Risk Factors , Smoking/genetics
8.
Am J Respir Crit Care Med ; 203(7): 799-801, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1088354
9.
Respirology ; 26(5): 442-451, 2021 05.
Article in English | MEDLINE | ID: covidwho-1032419

ABSTRACT

BACKGROUND AND OBJECTIVE: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. METHODS: We obtained lower AEC from 145 people from two independent cohorts, aged 2-89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. RESULTS: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. CONCLUSION: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.


Subject(s)
Asthma/genetics , COVID-19/genetics , Epithelial Cells/metabolism , Gene Expression Regulation , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2 , Asthma/epidemiology , Asthma/metabolism , Australia/epidemiology , COVID-19/epidemiology , COVID-19/metabolism , Comorbidity , Female , Humans , Male , Middle Aged , Peptidyl-Dipeptidase A/biosynthesis
10.
J Allergy Clin Immunol ; 146(2): 315-324.e7, 2020 08.
Article in English | MEDLINE | ID: covidwho-592253

ABSTRACT

BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.


Subject(s)
Asthma/epidemiology , Asthma/genetics , Coronavirus Infections/epidemiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Receptors, Virus/genetics , Adolescent , Adult , Angiotensin-Converting Enzyme 2 , Asthma/classification , Asthma/immunology , Betacoronavirus/genetics , Betacoronavirus/immunology , Biomarkers/metabolism , Bronchi/immunology , Bronchi/pathology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19 , Cohort Studies , Coronavirus Infections/virology , Eosinophils/immunology , Eosinophils/pathology , Female , Gene Expression Profiling , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Male , Middle Aged , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/virology , Protein Interaction Mapping , Receptors, Virus/immunology , Risk Factors , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/classification , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcriptome , United States/epidemiology
12.
Allergy ; 75(11): 2829-2845, 2020 11.
Article in English | MEDLINE | ID: covidwho-526792

ABSTRACT

BACKGROUND: Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19. METHODS: We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status. RESULTS: ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis. CONCLUSIONS: Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Basigin/immunology , COVID-19/epidemiology , Chronic Disease/epidemiology , Dipeptidyl Peptidase 4/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Age Factors , Aged , Angiotensin-Converting Enzyme 2/genetics , Asthma/epidemiology , Asthma/genetics , Asthma/immunology , Basigin/genetics , COVID-19/genetics , COVID-19/immunology , Child , Child, Preschool , Comorbidity , Dipeptidyl Peptidase 4/genetics , Female , Gene Expression/genetics , Humans , Hypertension/epidemiology , Hypertension/genetics , Hypertension/immunology , Immunity, Innate/immunology , Infant , Male , Middle Aged , Obesity/epidemiology , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/immunology , Risk Factors , SARS-CoV-2/genetics , Young Adult
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