The objective is to explore the role of histoblood group antigens in virus-induced asthma exacerbations. These antigens (ABH and Lewis) decorate O- and N-linked glycans on mucin and epithelial glycoproteins, respectively. Glycan synthesis involves glycosyltransferases, including fucosyltransferases encoded by FUT genes; glycan degradation involves glycosidases, including fucosidase. """"""""Secretor status"""""""" is defined by FUT2 activity in epithelial cells, which forms the H antigen and allows subsequent synthesis and secretion of A, B, and Lewis B antigens. In preliminary data, we found that asthmatic subjects with frequent exacerbations are more likely than non-exacerbators to be secretors, that secretors more frequently report that a cold causes asthma, and that sputum in stable asthma has abnormally high fucosidase activity. This suggests that airway glycans are subjected to 2 competing homoeostatic influences, a) the diversity and activity of glycosyltransferases within cells that synthesize glycans, and b) the diversity and activity of glycosidases that turn over and remodel them in the airway lumen. We hypothesize that secretor positive asthmatic subjects are susceptible to virus-induced asthma exacerbation and that abnormal glycosidase activity in secretions modifies the glycan coat and promotes virus-induced exacerbation.
In Aim 1, we propose a case control study to compare secretor status in hospitalized asthmatics and outpatient asthmatics without a history of exacerbation. The relationships between secretor status and FUT gene and histo-blood group antigen expression in airway epithelial cells will also be established.
In Aims 2 and 3, we will determine if binding of rhinovirus to airway mucins or to airway epithelial cells is influenced by secretor status or by fucosidase activity.
In Aim 4 we will determine if Th2 cytokines influence epithelial cell susceptibility to rhinovirus infection by changing epithelial cell expression of glycolytransferases or glycosidases. These are novel lines of inquiry into the mechanisms of virus-induced asthma exacerbation and may prompt novel treatments.
| Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386 |
| Dunican, Eleanor M; Elicker, Brett M; Gierada, David S et al. (2018) Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest 128:997-1009 |
| Lachowicz-Scroggins, Marrah E; Gordon, Erin D; Wesolowska-Andersen, Agata et al. (2018) Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity. Cell Discov 4:7 |
| MacNee, William; Fahy, John V; Nicod, Laurent P et al. (2017) Purpose of the Conference: The 2017 Transatlantic Conference on Lung Diseases. Ann Am Thorac Soc 14:S313 |
| Gordon, Erin D; Simpson, Laura J; Rios, Cydney L et al. (2016) Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A 113:8765-70 |
| Kerr, Sheena C; Fischer, Gregory J; Sinha, Meenal et al. (2016) FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection. PLoS Pathog 12:e1005555 |
| Lachowicz-Scroggins, Marrah E; Yuan, Shaopeng; Kerr, Sheena C et al. (2016) Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma. Am J Respir Crit Care Med 194:1296-1299 |
| Peters, Michael C; McGrath, Kelly Wong; Hawkins, Gregory A et al. (2016) Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med 4:574-584 |
| Fahy, John V (2016) Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress. Ann Am Thorac Soc 13 Suppl 1:S78-82 |
| MacNee, William; Fahy, John V; Nicod, Laurent P et al. (2016) Purpose of the Conference: 2016 Transatlantic Airway Conference. Ann Am Thorac Soc 13 Suppl 5:S395 |
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