[BAD] EK9 - Abstracts

Obesity dysregulates immunometabolic status in pediatric asthma and impacts vaccine responses
Sarah E. Henrickson1,2, Peyton Conrey2, Sasikanth Manne1,3, , Samir Sayed2, Kaitlin C. O’Boyle3 Bertram Bengsch1,†  , Ting Qian4, Ramin S. Herati1,5††­­†, Laura A. Vella1,6, Allison R. Greenplate1,3, Sam J.  McCright1,7, Cécile Alanio1,3, 12, Frank Mentch11, Kenneth E. Schmader8, Christopher F. Pastore9, Li-Yin Hun9, Scott E. Hensley1,10, De’Broski Herbert9, Aaron J. Masino4, Jorge Henao-Mejia1,7, Hakon Hakonarson11, Joshua D. Rabinowitz12, Susan E. Coffin6 and E. John Wherry1,3,12 
1Institute for Immunology, University of Pennsylvania, Philadelphia, PA.
2Division of Allergy-Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA.
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA.
4Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA.
5Department of Medicine, University of Pennsylvania Perelman School of Medicine 
6Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA. 
7Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA.
8Division of Geriatrics, Department of Medicine, Duke University Medical Center and Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC.
9School of Veterinary Medicine, Department of Pathobiology, University of Pennsylvania, Philadelphia. PA
10Department of Microbiology, University of Pennsylvania, Philadelphia, PA.
11Center for Applied Genomics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA.
12Parker Institute for Cancer Immunotherapy at University of Pennsylvania
13Department of Chemistry, Princeton University, Princeton, NJ.
†1Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany, and Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
††Department of Medicine, New York University, Grossman School of Medicine, New York City, NY.
 
Asthma and obesity are two of the most common chronic childhood diseases worldwide, with dramatically increasing prevalence over the last few decades. These diseases impact morbidity and mortality and strain health care systems financially. Asthma risk increases as body mass index (BMI) increases, suggesting a pathophysiological link. Both asthma and obesity are independently linked to altered immune status, however, it remains unclear how these diseases converge to affect pediatric immune function. To address this question, we investigated the immunometabolic profile in obese asthmatic (OA), non-obese asthmatic (A), obese non-asthmatic (O), and healthy control (HC) children using mass cytometry, serum metabolomics, cytokine analysis and clinical history. This multi-modal approach revealed two major forms of immune dysfunction in pediatric allergic OA: altered baseline T cell activation state (exhaustion-like) and increased type 2 immunity. OA had increased Th2 differentiation and decreased Th17 differentiation and these changes were associated with altered blood metabolites, including increased glutamate and decreased acetate. A mouse model of OA confirmed increased exhausted-like CD8 T cells compared to A and HC mice. Finally, immunometabolic dysregulation and altered T cell activation status in O and OA patients was linked to prolonged retention of humoral vaccine responses. These insights into the mechanistic links between metabolic alterations and immune dysfunction in OA may improve understanding of the severe asthma exacerbations secondary to viral upper respiratory tract infections seen in OA and provide opportunities for novel therapeutic approaches.

Asthma and comorbidities, a harmful association, especially during COVID-19
Leila Laouar1,2,*, Sarah Boukellal2, Ali Adib Yaici2, Med Taib Makhloufi1,2, and Samya Taright1,2
1University Benyoucef Benkhedda, School of Medicine, Algiers, Algeria.
2Department of Pulmonary Diseases, Center Hospitalo-Universitaire Mustapha Pasha, Algiers, Algeria
* Correspondence should be addressed to: laouar_leila@yahoo.fr
 
Asthma management cannot depend solely on medication; instead, it requires the control of environmental exposures as well as the comorbidities that have a poor impact on the overall prognosis. Among these comorbidities, cardiovascular manifestations and metabolic disorders such as diabetes and obesity, are reminiscent of the risk factors underlying COVID-19 severity. Management of such comorbidities is critical in asthmatic patients during a pandemic, and particularly during the confinement period in which sedentary lifestyle, depression and eating disorders significantly intensify, contributing to weight gain and induction of cardiovascular diseases in asthmatic patients. The goal from this study is to determine the frequency of comorbidities and their impact on asthma control. To this aim, we have conducted a study using a cohort of 51 asthmatic patients monitored in the Tuberculosis and Chronic Respiratory Diseases Control Unit at Mustapha Pasha Hospital in Algiers, Algeria. In agreement with data studies published in the literature, we observed that women are at significantly increased risk of developing asthma with a male to female ratio of 0.31 and a median patient age of 58 years. Our data revealed a poor control of asthma in 35% of our cohort patients compared to 25-65% of cases reported in the literature, but a higher frequency of comorbidities in 88.2% of our patients compared to 15-86% of cases reported in the literature. Specifically, we report the following medical conditions in our cohort patients: 30% obesity (among obese patients, 47% exhibited poor asthma control); 60% allergic rhinitis (among patients with rhinitis, 25% exhibited poor control); 27% gastroesophageal reflux disease or GERD (among patients with GERD, 35% exhibited poor control); 30% hypertension (among hypertensive patients, 38% exhibited poor control); and 12% type 2 diabetes (among diabetic patients, 54% exhibited poor control). It should be noted that asthma control is largely conditioned by the proper use of the inhalation device, which remains a problem for the majority of asthmatic patients. However, this is not the case for our cohort patients, since most of them (> 75%) were properly trained for the use of such a medical device. Finally, in agreement with data studies published in the literature, we observed that smoking -whether passive or active- caused further exacerbations of asthma with lesser disease control. Although asthma is not among the top conditions associated with COVID-19 deaths (unlike cardio-metabolic disorders which are more frequently reported in severe COVID-19 cases); we cannot rule out the possibility that infection by COVID-19 could be responsible for an exacerbation of asthma, in particular in the presence of comorbidities which are reminiscent of the risk factors of severity and mortality by COVID-19. In this regard, recent published data on Algerian patients hospitalized for severe forms of COVID-19 reported a frequency of 8% of asthmatics among COVID-19 patients. Notably, these COVID-19 asthmatics suffered from a severe form of asthma associated with cardiovascular comorbidities. Therefore, achieving an optimal level of asthma control should be among the primary goals to attenuate COVID-19 severity. However, such a control is arduous due to the many associated factors involved in a cause-effect relationship with asthma including allergic rhinitis, GERD and obesity, in addition to the most common comorbidities such as diabetes. With all data considered, it remains unsolved whether the reported severity of COVID-19 in asthmatics is due to asthma manifestation itself or is the result of its underlying comorbidities. Future studies in this direction will elucidate the bias of causal links of asthma with certain comorbidities in COVID-19 patients.

Modeling airway dysfunction in asthma using synthetic mucus biomaterials

As asthma worsens, occlusion of airways with mucus significantly contributes to airflow obstruction and reduced lung function. Recent evidence from clinical studies has shown mucus obtained from adults and children with asthma possesses altered mucin composition. However, how these changes alter the functional properties of the mucus gel is not yet fully understood. To study this, we have engineered a synthetic mucus biomaterial to closely mimic the properties of native mucus in health and disease. We demonstrate this model possesses comparable biophysical and transport properties to native mucus ex vivo collected from human subjects and in vitro isolated from human airway epithelial (HAE) tissue cultures. We found by systematically varying mucin composition that mucus gel viscoelasticity is enhanced when predominantly composed of mucin 5AC (MUC5AC), as is observed in asthma. As a result, asthma-like synthetic mucus gels are more slowly transported on the surface of HAE tissue cultures and at a similar rate to native mucus produced by HAE cultures stimulated with the type 2 cytokine IL-13, known to contribute to airway inflammation and MUC5AC hypersecretion in asthma. We also discovered the barrier function of asthma-like synthetic mucus towards influenza A virus was impaired as evidenced by the increased frequency of infection in MUC5AC-rich hydrogel coated HAE cultures. Together, this work establishes a biomaterial-based approach to understand airway dysfunction in asthma and related muco-obstructive lung diseases.

Glucagon-like Peptide-1 Receptor Agonists decrease type-2 biomarker in asthma

Dinah Foer1,2, Patrick Beeler3, Jing Cui1,2, Joshua A. Boyce1,2, Elizabeth Karlson1,2, David W. Bates1,2, Katherine Cahill4
1Brigham and Women's Hospital, 2Harvard Medical School, Boston, MA, 3University Hospital of Zurich, Zurich, Switzerland, 4Vanderbilt University Medical Center, Nashville, TN.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are approved for the treatment of type II diabetes mellitus (DMII) and obesity. In murine models, GLP-1RA inhibit allergen- and viral-induced airway inflammation including airway interleukin (IL)-33 release, IL-13 and mucus production and hyperresponsiveness. Observational patient data supports an association between GLP-1RA use and decreased asthma exacerbations in patients with asthma and DMII. We hypothesized that GLP-1RA would decrease biomarkers pertinent to airway inflammation pathways in patients with asthma. To test this hypothesis, we obtained serum samples from adults with asthma and comorbid DMII in the Partners HealthCare Biobank treated with (N=43) or without a GLP-1RA (N=119) at the time of sample collection. Demographics, body mass index, asthma severity, glucose control, and comorbidities, confirmed by electronic health record chart review were extracted and a propensity score calculated based on GLP-1RA use included as a covariate in a logistic regression model. Serum periostin, total IgE, IL-6, IL-8, IL-33 and sST2 levels were measured. Periostin (Padi=.0006) was significantly decreased in GLP-1RA users than non-GLP-1RA users which included use of basal insulin, SGLT-2 inhibitors or sulfonylureas. There were no significant differences in total IgE (Padj =.12), IL-6 (Padj =.62), IL-8 (Padj =.41), sCD163 (Padj=.53), IL-33 (Padj =.91), and sST2 (Padj =.90). Periostin results were robust across asthma severity and gender subgroup analyses. Serum periostin, a known systemic biomarker of Type (T)2 cytokines IL-4 and IL-13 in airway inflammation, is significantly and selectively decreased in adults with asthma and comorbid DMII treated with GLP-1RAs. Our results support a role for GLP-1R signaling in airway inflammation and point to periostin as a possible biomarker for therapeutic use of GLP-1RAs in asthma.

Funding: NIH AI118804, Brigham and Women’s Hospital Department of Medicine Innovation Evergreen Award, Brigham Research Institute Pilot Award

IL-13 regulates transcriptional changes in SARS-CoV-2-associated genes in asthma

Luke R Bonser1*, Walter L Eckalbar1,2,3*, Stephanie A Christenson2, Jiangshan Shen1, Kyung Duk Koh1, Lorna T Zlock4, Walter E Finkbeiner4, and David J Erle1,3,5,6

*These authors contributed equally.
1Lung Biology Center and 2Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine; 3UCSF CoLabs; 4Department of Pathology; 5Cardiovascular Research Institute; and 6ImmunoX Initiative; University of California, San Francisco

Rationale: SARS-CoV-2, the virus that causes COVID-19, exhibits an ACE2-dependent airway epithelial tropism, and exploits host cell proteins to replicate and evade detection. The impact of asthma on COVID-19 susceptibility and severity is unclear.

Objectives: We sought to discover how genes encoding SARS-CoV-2-associated host proteins are expressed in primary human bronchial epithelial cells (HBECs), and how these genes are regulated by cytokines important in asthma.

Methods: We cultured primary HBECs at air-liquid interface in the absence of cytokine, or with IL-13, IL-17, IFN-a, or IFN-g. We used bulk RNA-seq and single cell RNA-sequencing to identify changes in gene expression. We correlated cytokine-regulated changes in SARS-CoV-2-associated transcripts with gene expression changes in transcriptomic profiling datasets derived from individuals with mild-to-moderate asthma and chronic obstructive pulmonary disease (COPD).

Measurements and Main Results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 85 (26%) of these mRNAs were regulated by at least one cytokine (>1.5-fold change, FDR < 0.05). 21 and 19 of the 41 SARS-CoV-2-associated genes regulated by IL-13 in HBECs were correlated with type 2 inflammatory gene signature scores in transcriptomic profiling datasets derived from individuals with mild-to-moderate asthma and COPD (p < 0.05). Few IL-17 or interferon-responsive genes were correlated with their respective signatures in either dataset. Single cell RNA-sequencing revealed that 143 of the 332 (43%) SARS-CoV-2-associated transcripts detected in HBECs were differentially expressed between cell types (FDR < 0.05); some of these genes were associated with SARS-CoV-2 proteins predicted to co-opt host trafficking pathways. 11 SARS-CoV-2-associated genes were modulated by IL-13 in a cell type-specific manner (>1.25-fold change, FDR < 0.05).

Conclusions: Many genes encoding proteins associated with SARS-CoV-2 infection are expressed in HBECs, with substantial differences among cell subsets. IL-13 induces extensive changes in the expression of SARS-CoV-2-related genes that correlated with a measure of type-2 inflammation in vivo, providing a plausible basis for differences in outcome of COVID-19 in individuals with asthma.

RNA binding protein HuR posttranscriptionally regulates CD4+ T cell inflammatory gene expression in asthma
Ulus Atasoy1, Fatemeh Fattahi1, Jason Ellis1, Kristin Bahleda1, Nerissa Reister1, Njira Lugogo1,
1 University of Michigan, Ann Arbor, MI.

Due to poor correlation between steady-state mRNA levels and protein product, transcriptomic analyses may miss critical genes controlling inflammation. Many genes are regulated posttranscriptionally at levels of mRNA stability and translation by RNA-binding proteins (RBPs) and miRNAs, however this is not well understood. Pro-inflammatory genes which play pivotal roles in airway inflammation usually have labile mRNA transcripts and are regulated posttranscriptionally. Using novel RIP-Seq methods, we have uncovered how RBP HuR (elavl1) regulates key genes involved in CD4+ Th subset differentiation since it binds to and regulates gata3 and Th2 cytokine mRNAs. HuR regulates inflammatory genes allowing for lung inflammation in asthma. We previously demonstrated that HuR overexpression in CD4+ T cells results in increases in Th2 cytokine production. Conditional ablation of HuR in T cells (distal Lck-cre HuRfl/fl), abrogates Th2 differentiation, cytokine production and lung inflammation in ova challenge model. We hypothesized that HuR may similarly regulate lung inflammation in human asthma. We discovered that HuR protein expression is greatly increased (100%) in peripheral CD4+ T cells from asthmatics (both type 2 high and low) compared with healthy individuals. Asthmatic PBLs have increased frequency and production of both Th2/Th17 signature cytokines. Using a drug (acadesine aka AICAR) which interferes with HuR function, we show that CD4+ T cells treated with acadesine have decreases in Th2/17 cytokine expression. Taken together, these data suggest that HuR plays a permissive role in both allergen and non-allergen driven airway inflammation by regulating key genes and that interfering with its function may be a novel way to treat asthma.

Leukotriene E4 Rapidly Amplifies Airway Type 2 Inflammation Through IL-25 and Endogenous Cysteinyl Leukotrienes

Tao Liu 1,2, Lora G. Bankova1,2, Nora A. Barrett1,2, Chunli Feng1, Junrui Lin1, Juying Lai1, and Joshua A. Boyce 1,2,3
1Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital
Departments of 2Medicine and 3Pediatrics, Harvard Medical School
Boston, MA 02115
Abstract
Leukotriene E4 (LTE4), the stable metabolite of cysteinyl leukotrienes (cysLTs), accumulates in asthma, aspirin exacerbated respiratory disease (AERD) and chronic rhinosinusitis. Although it is the weakest direct bronchoconstrictor of the three cysLTs, LTE4 is disproportionately potent in the airways of subjects with asthma and AERD, and elicits both bronchial eosinophilia and mast cell (MC) activation when administered to asthmatic subjects by inhalation. We previously reported that LTE4 elicited expansion of IL-25-expressing tracheal brush cells (BrCs) and mild airway eosinophilia in naïve mice by a pathway requiring the type 3 cysteinyl leukotriene receptor (CysLT3R). We now report that LTE4 rapidly amplifies features of type 2 immunopathology by a pathway requiring all three cysLT receptors, and sequential actions of IL-25, IL-33, and endogenously generated LTC4.  A single inhaled dose of LTE4 administered to AERD-like Ptges-/- mice elicited rapid increases in lung ILC2s, PAS+ goblet cells, and DLCK1+ brush cells in the trachea.  LTE4 caused the rapid recruitment of platelet-adherent eosinophils to the lung, as well as sharp increases in airway resistance, release of mast cell activation products, and lung levels of IL-33. Deletion of CysLT3R, antibody neutralization of IL-25 and pharmacologic blockades of either CysLT1R or CysLT2R attenuated all features. Thus, LTE4 drives a potent innate type 2 response initiated by the bush cell products LTC4 and IL-25,  amplified by downstream ILC2 activation, and culminates in platelet-adherent eosinophil recruitment and platelet-dependent IL-33-driven mast cell activation. These findings suggest several avenues for therapeutic development, especially in AERD where the levels of LTE4 are especially high. 

Asthma and eosinophilia as predictors of outcomes in COVID-19 disease
William Collins MD*1,2, Ziyuan He PhD1, Lauren Eggert, MD3, Allie Lee1, Shu Cao1, Gopal Dhondalay PhD1, Tina Sindher MD1, Kari C Nadeau MD PhD1, R. Sharon Chinthrajah, MD1,3 
1Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, 2Department of Medicine, Division of Hospital Medicine, Stanford University School of Medicine, 3Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, Stanford University School of Medicine; *corresponding author
Rationale: There has been conflicting initial data regarding the effect of comorbid asthma on severity of illness with COVID-19 disease. Multiple studies have demonstrated an increased prevalence of asthma among hospitalized patients, but more recent studies have not shown an increased risk of severe infection in patients with asthma. Furthermore, the Th2 inflammation associated with the allergic asthma subtype can downregulate ACE-2 expression providing a potential protective effect. Our objective is to understand the impact of asthma and eosinophilia as predictors of disease outcomes in patients at Stanford Hospital infected with SARS-CoV-2  

Methods:  SARS-CoV-2 RT-PCR positive patients tested at Stanford Hospital were identified and hospitalization status, asthma history, demographics, co-existing conditions, laboratory values and COVID-19 severity were determined.  Inpatients were defined as those patients hospitalized within 14 days of a positive test for SARS-CoV-2. Patients were excluded from further analysis if they had no other documented clinical history or were younger than 28 days. COVID-19 disease severity was designated according to the 5-point NIH COVID-19 treatment guidelines.
 
Results:  From March 2 to September 30, 2020, 168,190 patients were tested for SARS-CoV-2 at Stanford Hospital and 6,976 (4.1%) tested positive. 1,380 patients were excluded from further analysis. Of the remaining 5,596 patients, 605 required hospitalization. Of the 605 hospitalized patients, 100 had a pre-existing diagnosis of asthma. History of asthma was significantly associated with COVID-19-related hospitalization (p<0.001, adjusted odds ratio = 1.52, 95%CI = [1.185-1.933]) in multivariate analysis adjusted for age, sex, and ethnicity. Additionally, older age, male sex, obesity (BMI>30) and asthma were significantly associated with clinical severity of COVID-19 in hospitalized patients in multivariate analysis (p<0.05). 801 SARS-CoV-2+ patients had historical eosinophil counts (HEC) available for analysis, and lower HEC was significantly associated with need for hospitalization when adjusted for both age and asthma status.    
 
Conclusions: In our cohort of patients tested for SARS-CoV-2 at Stanford, 605 were hospitalized at Stanford Hospital. Older age, male sex, obesity, and asthma were significantly associated with increased clinical severity of COVID-19 disease in hospitalized patients. Additionally, asthma and lower historical eosinophil counts were associated with need for hospitalization in certain sub-groups. Larger cohorts are needed to understand which factors in asthmatic patients contribute to more severe COVID-19 infection.

COVID-19 Admissions Associated with Asthma Related Diagnosis: A Closed Scheme Case Study

Background: The COVID-19 epidemic has adversely affected health systems globally. Most are overwhelmed because of the unprecedented spread of the virus. COVID-19 is a respiratory disease that impacts the respiratory tract which includes your lungs. When COVID-19 is severe it can bring on pneumonia or acute respiratory distress syndrome (ARDS). Chronic respiratory diseases (CRDs) are among the leading causes of death worldwide.  The World Health Organization (WHO) estimates that non-communicable disease (NCDs) represent 63% of all global deaths of which 3.9 million are due to CRDs and Chronic Obstructive Pulmonary Disease (COPD). The most common chronic respiratory diseases globally are asthma and chronic obstructive pulmonary disease and impact on the poor quality of life worldwide. Asthma is also amongst the top 5 most prevalent chronic conditions in medical schemes. Both asthma and COVID-19 are part of the Prescribed Minimum Benefits (PMB). There are various studies depict that asthma may increase the risk of hospitalization from COVID-19.  According to Wang et al. (2020), asthma as comorbidity may not increase the mortality of COVID-19. Further studies indicate no casual association between Asthma and COVID-19, it is also unclear whether patients with asthma are at a higher risk of developing COVID-19 and/or becoming severely ill.
 
Objectives: The objective of this study was to assess COVID-19 related admissions that are possibly associated with asthmatic diagnosis at discharge phase.
 
Methods: The study entailed a descriptive cross-section analysis of a closed medical scheme using claims information on COVID-19. Patients were included if they had laboratory-confirmed (RT – PCR assay) COVID-19 infection at admission phase and a hospital discharge primary diagnosis linked to Asthma.
Results: The analysis covered a total of 71 closed medical scheme patients that were admitted for COVID- 19 related diagnosis and primary diagnosis code linked to Asthma. The primary diagnosis for admission was used as a guide to identify a COVID-19 confirmed case or suspected case. The median age of patients admitted to hospital was 51 (IQR 44-60). The median number of inpatient days was seven (IQR 5-12). Significantly more of the patients were males, 85.92% vs. 14.02%, p <0.0001.
Nearly thirty percent of admissions were in General Ward, 29.58%, just under twenty percent were admitted in High Care, 18.31%. Less than two percent of admissions were in ICU, 1.41%, The reminder which was just over half were in other types admitting facilities which included home-based or outpatient care, 50.7%. Significantly more of the discharge diagnosis was liked to Asthma, unspecified which accounted for 92% of patients.
Conclusion: The study found evidence that restricted scheme patients admitted for COVID-19 had symptoms associated with Asthma. This finding further depicts some evidence of a link between COVID-19 and Asthma, which are both respiratory chronic conditions. Both these conditions are listed as PMBs by the CMS and that medical schemes must fund in full. The findings of this study indicate a further need for a more comprehensive analysis on the possible associations between asthma and COVID-19 infection and severity. These insights will further assist in efforts and interventions to support asthma care and better healthcare management.

ADAR-mediated editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma

Magnaye KM(1), Naughton KA(1), Huffman J(1), Hogarth DK(2), Naureckas ET(2), White SR(2), Ober C(1)
1. Department of Human Genetics, University of Chicago, Chicago, IL
2. Department of Medicine, University of Chicago, Chicago, IL

Asthma is a chronic lung disease characterized by persistent airway inflammation and bronchial hyperresponsiveness. Altered microRNA-mediated gene silencing in bronchial epithelial cells has been reported in asthma, yet microRNA adenosine to inosine (A-to-I) editing in asthma remains unexplored. We performed the first genome-wide analysis of ADAR-mediated microRNA editing using microRNA-seq in primary bronchial epithelial cells from 142 adult asthma cases and non-asthma controls. Of 19 A-to-I edited sites detected in these microRNAs, 16 were in seed regions. Four of the 16 edited sites were observed in >10 individuals and were tested for differential editing (% A-to-I) between groups. One site at position 5 of miR-200b-3p was edited less frequently in asthma cases compared to controls (P = 0.013). A-to-I editing of this site was then compared between asthma severity groups (mild, moderate and severe) based on lung function and medication use. The moderate (P = 0.037) and severe (P = 0.00031), but not mild (P = 0.77), asthma cases had significantly less A-to-I editing of the 5th position of miR-200b-3p compared to controls. Bioinformatic prediction revealed 232 in silico target genes of the edited miR-200b-3p, which were enriched for both IL-4 and interferon gamma signaling pathways and included the SOCS1 (suppressor of cytokine signaling 1) gene. SOCS1 was more highly expressed in moderate (P = 0.017) and severe (P = 0.0054) asthma cases compared to controls. Moreover, both miR-200b-3p editing and SOCS1 were associated with BAL eosinophil levels and an epithelial cell signature of Type 2 asthma. Overall, reduced ADAR-mediated editing of the 5th position of miR-200b-3p in lower airway cells from moderate-to-severe asthmatics may lead to overexpression of a centrally important negative regulator of cytokine signaling, SOCS1. We proposed ADAR-mediated editing as an epigenetic mechanism contributing to features of moderate-to-severe asthma in adulthood. Supported by U19 AI095230. KMM is supported by F31 HL143891.