Type 2 Immune Development Depends on MARCH1-mediated MHCII and CD86 Turnover in Lymph Node Resident Dendritic Cells
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Type 2 Immune Development Depends on MARCH1-mediated MHCII and CD86 Turnover in Lymph Node Resident Dendritic Cells Authors: Carlos A. Castellanos (1), Xin Ren (2), Hong-Erh Liang (3), Brian J. Laidlaw (4), Satoshi Ishido (5), Jason G. Cyster (4), Richard M. Locksley (3), Xiaozhu Huang (2), and Jeoung-Sook Shin (1) Affiliations: (1) Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158, USA. (3) Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Department of Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Microbiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Abstract: Th2 cells protect host from parasitic worm infection but also aggravate allergic inflammatory diseases including asthma. The role of dendritic cells (DCs) in Th2 cell development is well established, yet underlying mechanisms are unclear. We found that development of Th2 cells by DCs depends on membrane-associated RING-CH1 (MARCH1), an E3 ligase that mediates ubiquitination and endolysosomal degradation of MHCII and CD86. Mice lacking MARCH1 in DCs failed to develop Th2 cells against environmental allergens and parasitic worms although they remained competent at developing Th1 and cytotoxic T cells against influenza. While Th2 cell development often associates with DC migration to the draining lymph node, MARCH1 was barely expressed in migratory DCs, and the effect of MARCH1 in promoting Th2 cell development was not dependent on migratory DCs. Moreover, a DC migration blockade did not impair the expression of GATA3 in developing Th2 cells in the lymph node while MARCH1 deficiency did, suggesting MARCH1 promotes Th2 cell development through its expression in the lymph node-resident DCs. MARCH1 deficiency resulted in 7-10 fold increase in MHCII and CD86 in the lymph node-resident DCs. Mice with mutations in the ubiquitin acceptor amino acids of MHCII and CD86 also showed marked accumulation of these molecules in the lymph node-resident DCs and exhibited poor induction of GATA3 in developing Th2 cells and poor Th2 cell inflammation in allergen-exposed airway. Thus, development of Th2 cell immunity depends on ubiquitin-mediated control of antigen presenting and costimulatory molecules in lymph node-resident DCs.
Speaker(s):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.
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Epidermal growth factor receptor in airway remodeling during allergic airway disease – divergent roles during early life and adulthood?
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Epidermal growth factor receptor in airway remodeling during allergic airway disease – divergent roles during early life and adulthood? H. Stölting, S. A. Walker, M. C. Zarcone, F. Puttur, S. Saglani, C. M. Lloyd National Heart and Lung Institute, Imperial College London - London (United Kingdom) Airway remodelling is a key pathological feature of paediatric and adult asthma, but the underlying mechanisms remain poorly understood. However, their elucidation is crucial, since lung function deficits established in children with asthma persist into adulthood. Epidermal growth factor receptor (EGFR) was shown to be overexpressed in paediatric and adult asthmatics. In addition, several in vivo studies using rodent models of allergic airway disease (AAD) have described a role for EGFR signalling in driving impaired lung function and airway remodelling in adult animals. Here, we aimed to study the role of EGFR in early life AAD. Bronchial epithelial cells from non-asthmatic children cultured at air-liquid interface were shown to exhibit high mRNA levels for EGFR and its ligands. Exposure of these cells to the allergen house dust mite induced EGFR activation dose-dependently, as measured by Y1068 phosphorylation. qPCR analysis of flow-sorted murine lung cell populations during postnatal development similarly showed high EGFR expression in murine lung epithelial cells from neonatal and adult mice, and lung epithelial EGFR expression was confirmed by flow cytometry. Finally, a pharmacological inhibitor was used to block EGFR signalling in a neonatal model of AAD. Preliminary findings indicate that EGFR inhibition in neonatal mice resulted in worsened lung function, as measured by a 2-fold increase in airway resistance (AUC), without affecting overall inflammation, a finding we did not observe in a corresponding adult AAD model. These results indicate that EGFR is present in lungs at all stages of life and that, in contrast to its widely described pathogenic contribution to airway remodelling of adult animals, signalling through EGFR may play a protective role during early life AAD.
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ADAR-mediated editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma
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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.
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Genetic analysis in mice reveals polygenic basis and candidate transcriptional regulators of airway remodeling features
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Genetic analysis in mice reveals polygenic basis and candidate transcriptional regulators of airway remodeling features AUTHORS: Lauren Donoghue1,2, Kathryn McFadden1, Greg Keele1, and Samir Kelada1,2,3 1Department of Genetics, University of North Carolina at Chapel Hill 2Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill 3Marisco Lung Institute, University of North Carolina at Chapel Hill BACKGROUND: Airway wall remodeling in individuals with asthma is thought to contribute to hallmark disease features and is associated with disease severity. Identifying the biological drivers of remodeling features and potential therapeutic targets remains challenging given the invasive nature of characterizing remodeling in patients. Numerous studies have shown that genetic variation plays a significant role in asthma risk, but the extent to which genetics may regulate airway remodeling has not been thoroughly investigated. We used systems genetics approaches in a population of genetically diverse mice chronically exposed to allergen to identify the genetic and transcriptomic underpinnings of variation in remodeling features. METHODS: The Collaborative Cross (CC) is a panel of recombinant inbred mouse strains whose genomes vary by over 45 million genetic variants. We chronically exposed BALB/cJ mice and 31 CC strains to saline or house dust mite allergen (25ug intra-nasally, 3x/week for 5 weeks) to induce airway inflammation and remodeling. We performed morphometric analysis of mucous cell metaplasia, subepithelial fibrosis, and smooth muscle thickening in addition to profiling inflammatory cells and mucin proteins in lavage fluid. For each phenotype, we estimated the contribution of genetic variation to overall phenotypic variation (heritability). Select strains were assessed for airway hyperresponsiveness. We performed RNAseq on airway tissue and integrative gene expression analyses including co-expression, eQTL mapping, and differential expression to identify phenotype-associated gene networks and candidate transcriptional regulators. RESULTS: The majority of CC strains exhibited remodeling and inflammation either more or less extreme than the oft-used BALB/cJ strain. Across CC strains, phenotypic outcomes were continuously distributed, indicative of polygenic architectures for each trait. Pairwise correlations between remodeling and inflammatory features varied from non-significant to r=0.37, suggesting remodeling is driven by both trait-shared and trait-specific molecular mechanisms. Through gene expression analyses we identified gene co-expression modules significantly associated with one or more remodeling traits and enriched for disease-associated pathways such as endoplasmic reticulum stress and TGFb-1 signaling. Genes highly-interconnected in modules included those differentially expressed in human asthma, near GWAS loci for asthma or lung function, and/or with unknown roles in disease. We identified candidate transcriptional regulators for subepithelial collagen deposition from co-expression modules enriched for expression in epithelial cells, fibroblasts, and plasma cells. CONCLUSIONS: Our results highlight that genetic variation significantly influences features of airway remodeling in the context of chronic allergen exposure in mice. Furthermore, remodeling traits have shared and distinct mechanisms of regulation that can be associated with gene expression programs containing genes with unknown functional roles. CC strains identified as having more extreme responses than BALB/cJ mice represent new models for the investigation of airway remodeling or severe asthma.
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CD4 Tissue Resident Memory T Cells Promote Inflammatory Pathways Associated with Asthma
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CD4 Tissue Resident Memory T Cells Promote Inflammatory Pathways Associated with Asthma Nathan Schoettler1, Anne I Sperling1, Carole Ober2 1University of Chicago, Department of Medicine; 2University of Chicago, Department of Human Genetics Activated CD4 T cells drive asthma pathogenesis through distinct cytokine and inflammatory pathways that have been linked to asthma phenotypes. These include Th2 and Th17 cytokines and IL-2, which drives antigen-specific T cell proliferation. However, the specific subset(s) of human lung CD4 T cells that contributes to these responses and how these T cells are activated is unknown. Features of human CD4 memory T cells differ between the lung and other sites, including higher expression of innate immune receptors, different proportion of memory subsets and distinct T cell receptor repertoires. We have characterized the responses of human lung CD4 effector memory (TEM) and tissue resident memory (TRM) T cell subsets to innate stimuli (lipopolysaccharide and poly-I:C, separately) and T cell receptor (TCR)-specific activation (anti-CD3/anti-CD28) in a total lung leukocyte cell culture model from 10 lung donors. After 20 hours of treatment, CD4 TEM and TRM T cells were sorted and RNA was extracted and sequenced for comparison of the transcriptional differences between cell types and between treatments. While there were no differences in gene expression responses between CD4 TEM and TRM cells after lipopolysaccharide or poly-I:C treatment at a false discovery rate of 5%, 424 genes were differentially expressed between CD4 TEM and TRM cells after anti-CD3/anti-CD28 treatment. Genes with higher expression in CD4 TRM cells included IL2, Th2 cytokines (IL4, IL13 and IL5) and the Th17 cytokine IL17A. Our results demonstrate that human CD4 TRM cells promote asthma-relevant responses after TCR-specific activation and that innate stimulation alone or TCR-specific activation of CD4 TEM cells does not activate these responses.
Speaker(s):Distribution of ACE2, CD147, CD26 and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors Radzikowska U. 1,2,3*, Ding M. 1,2,4*, Tan G. 1,5, Zhakparov D. 1, Peng Y. 1,2,6, Wawrzyniak P. 1,2,7, Wang M. 1,2,8, Li S. 1,9, Morita H. 1,10, Altunbulakli C. 1,2, Reiger M. 11, Neumann AU. 11,12,13, Lunjani N. 1,2, Traidl-Hoffmann C. 2,11, Nadeau K. 14, O’Mahony L. 1,15, Akdis CA. 1,2, Sokolowska M. 1,2 *equal contribution Affiliations 1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; 2 Christine Kühne – Center for Research and Education (CK-CARE), Davos, Switzerland; 3 Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland; 4 Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, China; 5 Functional Genomic Centre Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland; 6 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 7 Division of Clinical Chemistry and Biochemistry, University Children`s Hospital Zurich, Zurich, Switzerland; Children`s Research Center, University Children`s Hospital Zurich, Zurich, Switzerland; 8 Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University and the Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China 9 Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 10 Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; 11 Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and Helmholtz Zentrum Munchen, Augsburg, Germany; 12 Institute of Computational Biology (ICB), Helmholtz Zentrum Munchen, Munich, Germany; 13 Institute of Experimental Medicine (IEM), Czech Academy of Sciences, Prague, Czech Republic; 14 Sean N Parker Centre for Allergy and Asthma Research at Stanford University, Department of Medicine, Stanford University School of Medicine, Stanford, USA; 15 Department of Medicine and School of Microbiology, APC Microbiome Ireland, National University of Ireland, Cork, Ireland 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), 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 and PPIB), 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 ACE2- and 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 with age, gender, obesity and smoking, as well as with the disease status might contribute to COVID-19 morbidity and severity patterns.
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Defining the functions of tissue-resident and circulating memory Th2 cells in allergic asthma
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Defining the functions of tissue-resident and circulating memory Th2 cells in allergic asthma Rod A. Rahimi1,2,3, Keshav Nepal1,2,4, Murat Cetinbas5,6, Ruslan I. Sadreyev5,7, and Andrew D. Luster1,2,4 1Airway Immunity Research Program, 2Center for Immunology and Inflammatory Diseases, 3Division of Pulmonary and Critical Care Medicine, 4Division of Rheumatology, Allergy, and Immunology, 5Department of Molecular Biology, 6Department of Genetics, 7Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA Tissue-resident memory T (Trm) cells are a unique population of memory T cells that are durably parked in non-lymphoid tissues and play an important role in host defense against recurrent infection and malignancy. CD4+ T helper type 2 (Th2) cells play a central role in allergic diseases, including asthma, but the biology of Th2 Trm cells in recurrent allergic inflammation is not well defined. Specifically, the mechanisms whereby Th2 Trm cells and circulating memory Th2 cells promote allergic asthma pathogenesis remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform distinct functions in vivo. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote inflammatory cell recruitment, including CD4+ T cells, eosinophils, and dendritic cells. In contrast, Th2 Trm cells proliferated near airways and were critical in promoting mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm cells and circulating memory Th2 cells share a core Th2 gene signature, but also exhibit distinct transcriptional profiles. Th2 Trm cells express a tissue-adaptation signature, including genes involved in extracellular matrix biology and lipid metabolism. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in vivo, with the establishment of Th2 Trm cells being critical for the full manifestation of allergic airway disease. Defining the unique mechanisms regulating the development and maintenance of Th2 Trm cells within the lungs has the potential to yield novel therapeutic approaches for allergic asthma.
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Asthma triggers upregulate the expression and directly cleave GSDMB
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Asthma triggers upregulate the expression and directly cleave GSDMB Ronald Allan M. Panganiban1, Michael O’Sullivan1, Mengyuan Kan2, Blanca Himes2, Jin-ah Park1, and Quan Lu1 1Program in Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115 2Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania Asthma is a complex airway disease caused by a poorly understood interplay between environmental and genetic factors. Genome-wide association studies (GWAS) have identified numerous asthma-associated genes including GSDMB, a gasdermin family member that resides in 17q21 locus, the strongest and most replicated asthma GWAS signal. However, the functional role of GSDMB in asthma remains incompletely understood. Our previous work demonstrated that 1) caspase-1 cleaves GSDMB to liberate the N-terminal fragment which induces pyroptosis, a recently characterized mode of pro-inflammatory cell death; 2) a functional splice variant of GSDMB (rs11078928) associated with lower asthma risk abolishes GSDMB’s ability to induce pyroptosis; and 3) GSDMB is highly expressed in the airway epithelium, the airway’s first line of defense against asthma triggers. While these findings strongly implicate GSDMB as a bona fide asthma gene that mediates airway epithelial pyroptosis, it remains unclear how and whether asthma triggers affect GSDMB expression and function. Using in vitro cleavage assay, we show that GSDMB is cleaved directly by house dust mite (HDM), mold, and cockroach extracts. We also show that the GSDMB cleavage site for HDM is different from the cleavage site for caspase-1, which we previously demonstrated to be at Asp236. On the other hand, treatment of human bronchial epithelial cells cultured at the air-liquid interface (HBE-ALI) with rhinovirus A (RVA), but neither mechanical compression nor HDM, induces ~2 fold increase in GSDMB expression compared to untreated control. GSDMB promoter analysis by ContraV3 identifies a GATA-2 consensus binding site within the 1.0 kb promoter region upstream of GSDMB transcription start site suggesting that RVA possibly induces the transcription factor GATA-2 to promote GSDMB expression. Our data provides clues to the effect of different asthma triggers on GSDMB and reveals insights into the possible mechanistic link between asthma triggers and airway epithelial pyroptosis. Future studies are aimed at identifying the specific GSDMB cleavage sites for the asthma triggers, identifying the specific proteases in the asthma trigger extracts capable of cleaving GSDMB, as well as investigating the effects of multiple exposures to asthma triggers (e.g. RVA and HDM extracts) on GSDMB and pyroptosis.
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Asthma and eosinophilia as predictors of outcomes in COVID-19 disease
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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 (p30) and asthma were significantly associated with clinical severity of COVID-19 in hospitalized patients in multivariate analysis (p
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