Down syndrome is associated with altered frequency and functioning of tracheal multiciliated cells, and response to influenza virus infection
Samantha N. Thomas,
Brian F. Niemeyer,
Rocio J. Jimenez-Valdes,
Alexander J. Kaiser,
Joaquin M. Espinosa,
Kelly D. Sullivan,
Andrew Goodspeed,
James C. Costello,
Jonathan K. Alder,
Rodrigo Cañas-Arranz,
Adolfo García-Sastre,
Kambez H. Benam
Affiliations
Samantha N. Thomas
Department of Bioengineering, University of Colorado Denver, Aurora, CO 80045, USA
Brian F. Niemeyer
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rocio J. Jimenez-Valdes
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Alexander J. Kaiser
Department of Bioengineering, University of Colorado Denver, Aurora, CO 80045, USA
Joaquin M. Espinosa
Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kelly D. Sullivan
Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Andrew Goodspeed
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
James C. Costello
Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Jonathan K. Alder
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rodrigo Cañas-Arranz
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Adolfo García-Sastre
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Kambez H. Benam
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author
Summary: Individuals with Down syndrome (DS) clinically manifest severe respiratory illnesses; however, there is a paucity of data on how DS influences homeostatic physiology of lung airway, and its reactive responses to pulmonary pathogens. We generated well-differentiated ciliated airway epithelia using tracheas from wild-type and Dp(16)1/Yey mice in vitro, and discovered that Dp(16)1/Yey epithelia have significantly lower abundance of ciliated cells, an altered ciliary beating profile, and reduced mucociliary transport. Interestingly, both sets of differentiated epithelia released similar quantities of viral particles after infection with influenza A virus (IAV). However, RNA-sequencing and proteomic analyses revealed an immune hyperreactive phenotype particularly for monocyte-recruiting chemokines in Dp(16)1/Yey epithelia. Importantly, when we challenged mice in vivo with IAV, we observed immune hyper-responsiveness in Dp(16)1/Yey mice, evidenced by higher quantities of lung airway infiltrated monocytes, and elevated levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid. Our findings illuminate mechanisms underlying DS-mediated pathophysiological changes in airway epithelium.
