Rhinovirus Infections in Individuals with Asthma Increase ACE2 Expression and Cytokine Pathways Implicated in COVID-19.
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ABSTRACT:
SUBMITTER: Chang EH
PROVIDER: S-EPMC7462393 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We present evidence that (1) viral respiratory infections are potential mechanisms of ACE2 overexpression in patients with asthma and (2) ACE activation regulates multiple cytokine anti-viral responses that could explain a mechanism for cytokine surge and associated tissue damage. These results suggest that the recent finding of severe COVID-19 in asthma patients with recent exacerbations may be attributable to synergistic biomolecular interactions with viral co-infections.
2020-04-25 | GSE149273 | GEO
Project description:RV infections in asthmatics increase ACE2 expression and stimulate cytokine pathways implicated in COVID19
| PRJNA627860 | ENA
Project description:Rhinovirus infections can cause wheezing illnesses in all age groups. In preschool children, rhinovirus infections frequently initiate acute wheezing illnesses. Children who wheeze with rhinoviruses are at increased risk to go on to develop asthma. Once asthma is established, rhinovirus infections are potent triggers for acute airway obstruction and exacerbations in children and adults. Paradoxically, for most individuals, rhinovirus infections commonly cause cold symptoms with little or no involvement of the lower airways. This paradox has led investigators to identify specific risk factors and mechanisms for rhinovirus wheezing, and this review will outline progress in 3 main areas. First, the 3 species of rhinoviruses have different patterns of infection and virulence. Second, personal factors such as lung function and immunity influence lower respiratory outcomes of rhinovirus infection. The mucosal immune response is critical, and the quality of the interferon response and allergic inflammation interacts to determine the risk for rhinovirus wheezing. Finally, rhinovirus infections can promote pathogen-dominated airway microbiota that increase the risk for wheezing. Although specific antivirals for rhinovirus are still not available, identifying risk factors for wheezing illnesses has provided several other potential targets and strategies for reducing the risk of rhinovirus-induced wheezing and exacerbations of asthma.
| S-EPMC10314805 | biostudies-literature
Project description:RationaleAllergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal.ObjectivesTo test whether omalizumab treatment to reduce IgE would shorten the frequency and duration of rhinovirus (RV) illnesses in children with allergic asthma.MethodsIn the PROSE (Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations) study, we examined children with allergic asthma (aged 6-17 yr; n = 478) from low-income census tracts in eight U.S. cities, and we analyzed virology for the groups randomized to treatment with guidelines-based asthma care (n = 89) or add-on omalizumab (n = 259). Weekly nasal mucus samples were analyzed for RVs, and respiratory symptoms and asthma exacerbations were recorded over a 90-day period during the fall seasons of 2012 or 2013. Adjusted illness rates (illnesses per sample) by treatment arm were calculated using Poisson regression.Measurements and main resultsRVs were detected in 97 (57%) of 171 exacerbation samples and 2,150 (36%) of 5,959 nonexacerbation samples (OR, 2.32; P < 0.001). Exacerbations were significantly associated with detection of rhinovirus C (OR, 2.85; P < 0.001) and rhinovirus A (OR, 2.92; P < 0.001), as well as, to a lesser extent, rhinovirus B (OR, 1.98; P = 0.019). Omalizumab decreased the duration of RV infection (11.2 d vs. 12.4 d; P = 0.03) and reduced peak RV shedding by 0.4 log units (95% confidence interval, -0.77 to -0.02; P = 0.04). Finally, omalizumab decreased the frequency of RV illnesses (risk ratio, 0.64; 95% confidence interval, 0.49-0.84).ConclusionsIn children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses. These findings provide direct evidence that blocking IgE decreases susceptibility to RV infections and illness. Clinical trial registered with www.clinicaltrials.gov (NCT01430403).
| S-EPMC5649984 | biostudies-literature
Project description:BackgroundEarly-life wheezing-associated respiratory tract infection by rhinovirus (RV) is a risk factor for asthma development. Infants are infected with many different RV strains per year.ObjectiveWe previously showed that RV infection of 6-day-old BALB/c mice induces a mucous metaplasia phenotype that is dependent on type 2 innate lymphoid cells (ILC2s). We hypothesized that early-life RV infection alters the response to subsequent heterologous infection, inducing an exaggerated asthma-like phenotype.MethodsWild-type BALB/c mice and Rorafl/flIl7rcre mice lacking ILC2s were treated as follows: (1) sham on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 plus RV-A2 on day 13, and (4) RV-A1B on day 6 plus RV-A2 on day 13.ResultsMice infected with RV-A1B at day 6 and sham at day 13 showed an increased number of bronchoalveolar lavage eosinophils and increased expression of IL-13 mRNA but not expression of IFN-γ mRNA (which is indicative of a type 2 immune response), whereas mice infected with sham on day 6 and RV-A2 on day 13 of life demonstrated increased IFN-γ expression (which is a mature antiviral response). In contrast, mice infected with RV-A1B on day 6 before RV-A2 infection on day 13 showed increased expression of IL-13, IL-5, Gob5, Muc5b, and Muc5ac mRNA; increased numbers of eosinophils and IL-13-producing ILC2s; and exaggerated mucus metaplasia and airway hyperresponsiveness. Compared with Rorafl/fl mice, Rorafl/flIl7rcre mice showed complete suppression of bronchoalveolar lavage eosinophils and mucous metaplasia.ConclusionEarly-life RV infection alters the response to subsequent heterologous infection, inducing an intensified asthma-like phenotype that is dependent on ILC2s.
| S-EPMC8097639 | biostudies-literature
Project description:Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the HumanMethylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.
| S-EPMC6261460 | biostudies-literature
Project description:Rhinovirus (RV) is ubiquitous and typically causes only minor upper respiratory symptoms. However, especially in children and adolescent asthmatics, RV is responsible for most exacerbations. This ability of RV to drive exacerbations typically requires the concomitant presence of exposure to a bystander allergen. Susceptibility to RV-mediated exacerbations is also related to the genetic background of the host, which contributes to greater infectivity, more severe infections, altered immune responses, and to greater inflammation and loss of asthma control. Given these responses, there are several treatments available or being developed that should improve the control of exacerbations related to RV infection.
| S-EPMC6625523 | biostudies-literature
Project description:BackgroundRhinovirus (RV) infections are a major cause of asthma exacerbations. Unlike other respiratory viruses, RV causes minimal cytotoxic effects on airway epithelial cells and cytokines play a critical role in its pathogenesis. However, previous findings on RV-induced cytokine responses were largely inconsistent. Thus, this study sought to identify the cytokine/chemokine profiles induced by RV infection and their correlations with airway inflammatory responses and/or respiratory symptoms using systematic review, and to determine whether a quantitative difference exists in cytokine levels between asthmatic and healthy individuals via meta-analysis.MethodsRelevant articles were obtained from PubMed, Scopus, and ScienceDirect databases. Studies that compared RV-induced cytokine responses between asthmatic and healthy individuals were included in the systematic review, and their findings were categorized based on the study designs, which were ex vivo primary bronchial epithelial cells (PBECs), ex vivo peripheral blood mononuclear cells (PBMCs), and human experimental studies. Data on cytokine levels were also extracted and analyzed using Review Manager 5.4.ResultsThirty-four articles were included in the systematic review, with 18 of these further subjected to meta-analysis. Several studies reported the correlations between the levels of cytokines, such as IL-8, IL-4, IL-5, and IL-13, and respiratory symptoms. Evidence suggests that IL-25 and IL-33 may be the cytokines that promote type 2 inflammation in asthmatics after RV infection. Besides that, a meta-analysis revealed that PBECs from children with atopic asthma produced significantly lower levels of IFN-β [Effect size (ES): -0.84, p = 0.030] and IFN-λ (ES: -1.00, p = 0.002), and PBECs from adult atopic asthmatics produced significantly lower levels of IFN-β (ES: -0.68, p = 0.009), compared to healthy subjects after RV infection. A trend towards a deficient production of IFN-γ (ES: -0.56, p = 0.060) in PBMCs from adult atopic asthmatics was observed. In lower airways, asthmatics also had significantly lower baseline IL-15 (ES: -0.69, p = 0.020) levels.ConclusionOverall, RV-induced asthma exacerbations are potentially caused by an imbalance between Th1 and Th2 cytokines, which may be contributed by defective innate immune responses at cellular levels. Exogenous IFNs delivery may be beneficial as a prophylactic approach for RV-induced asthma exacerbations.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=184119, identifier CRD42020184119.
| S-EPMC8886024 | biostudies-literature
Project description:BackgroundBecause respiratory tract infections (RTIs) precede most exacerbations, a better understanding of the risk factors of RTIs and RTI-associated exacerbations in patients with asthma is a pressing public health need. Obesity in patients with asthma is associated with worse asthma control and higher asthma-associated health care utilization, but its effect on RTI risk is unknown.ObjectiveWe aimed to study the association of body mass index (BMI) classification on the risk of self-reported RTIs and related asthma morbidity among adults and children with asthma.MethodsThis post hoc analysis of 5 large asthma trials involving 747 children and 1287 adults compared BMI classification, defined as lean, overweight, and obese based on age-appropriate BMI and BMI-percentile conventions. The primary outcome was rate of visits with RTIs. Secondary asthma outcomes included upper respiratory infection (URI) severity, systemic steroid use, and health care contact.ResultsChildren had 1.4 times the rate of RTI compared with adults (95% confidence interval 1.27-1.56). In all participants, BMI classification did not affect the rate of visits with RTI. In children, BMI classification did not affect URI severity, all-cause asthma events, or RTI-associated asthma events. However, in adults, higher BMI classification was associated with an increase in moderate/severe URI (P = .02). Adults with higher BMI classification also had increased rates of all-cause and RTI-associated asthma exacerbations requiring systemic steroids and health care contact.ConclusionsBMI classification was not associated with an increased risk of RTIs in children or adults. In adults only, obesity was associated with increased URI severity and all-cause and RTI-associated asthma morbidity.
| S-EPMC6609096 | biostudies-literature
Project description:CDHR3 (cadherin-related family member 3) is a transmembrane protein that is highly expressed in airway epithelia and the only known receptor for rhinovirus C (RV-C). A CDHR3 SNP (rs6967330) with G to A base change has been linked to severe exacerbations of asthma and increased susceptibility to RV-C infections in young children. The goals of this study were to determine the subcellular localization of CDHR3 and to test the hypothesis that CDHR3 asthma-risk genotype affects epithelial cell function and susceptibility to RV-C infections of the airway epithelia. We used immunofluorescence imaging, Western blot analysis, and transmission electron microscopy to show CDHR3 subcellular localization in apical cells, including expression in the cilia of airway epithelia. Polymorphisms in CDHR3 rs6967330 locus (G→A) that were previously associated with childhood asthma were related to differences in CDHR3 expression and epithelial cell function. The rs6967330 A allele was associated with higher overall protein expression and RV-C binding and replication compared with the rs6967330 G allele. Furthermore, the rs6967330 A allele was associated with earlier ciliogenesis and higher FOXJ1 expression. Finally, CDHR3 genotype had no significant effects on membrane integrity or ciliary beat function. These findings provide information on the subcellular localization and possible functions of CDHR3 in the airways and link CDHR3 asthma-risk genotype to increased RV-C binding and replication.
| S-EPMC6775945 | biostudies-literature