In cystic fibrosis (CF), a defect in mucosal defenses leads to airway colonization with bacteria, inflammation, remodeling, and tissue destruction. The disease is progressive and life limiting. Recent studies indicate that loss of CFTR function reduces bicarbonate permeability across the airway epithelium and lowers the pH of airway surface liquid (ASL), impairing the function of secreted host defense factors. This may be among the earliest events favoring colonization. Respiratory viral infections may also contribute to development of lung disease in infants and children with CF. Epidemiologic data indicate that respiratory virus infections cause prolonged symptoms in children with CF, induce exacerbations, and enhance bacterial colonization. While clinical studies and limited in vitro data suggest the possibility of altered responses to viruses in CF, this is an experimentally difficult problem to study in humans. Our central hypothesis is that virus infections contribute to disease onset and progression in CF. The CF pig model manifests a respiratory tract host defect at birth and spontaneously develops lung disease with many similarities to human infants with CF. The objective of. our studies is to use this model to investigate the contribution of virus infections to early CF lung disease. We will test our central hypothesis, using model virus infections and by pursuing the following three specific aims:
Aim 1. Do CFTR dependent changes in ASL environment allow respiratory viruses to infect airway epitheliamore readily? ? Aim 2. Do changes in interferon induction and responsiveness enhance respiratory virus infections in CF? Aim 3. Does CF alter the resolution phase ofthe response to respiratory virus infections? Leveraging the porcine CF model to study CF and non-CF responses to viral infections in vitro and in vivo is a novel approach to investigate human disease mechanisms. These complementary strategies should provide new insights into the early steps in CF lung disease pathogenesis that will inform future therapeutic strategies.

Public Health Relevance

Factors contributing to the early onset and progression of cystic fibrosis lung disease remain incompletely understood, preventing advances in new therapies. We hypothesize that respiratory virus infections contribute to disease onset and progression in CF. Using a novel pig model of CF, we will investigate the roles of respiratory viruses to the initiation and perpetuation of the earliest stages of lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
Park, Jung-Eun; Li, Kun; Barlan, Arlene et al. (2016) Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc Natl Acad Sci U S A 113:12262-12267
Cooney, Ashley L; Abou Alaiwa, Mahmoud H; Shah, Viral S et al. (2016) Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight 1:
Gibson-Corley, Katherine N; Meyerholz, David K; Engelhardt, John F (2016) Pancreatic pathophysiology in cystic fibrosis. J Pathol 238:311-20
Li, Xiaopeng; Tang, Xiao Xiao; Vargas Buonfiglio, Luis G et al. (2016) Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense. Am J Physiol Lung Cell Mol Physiol 310:L670-9
Shah, Viral S; Meyerholz, David K; Tang, Xiao Xiao et al. (2016) Airway acidification initiates host defense abnormalities in cystic fibrosis mice. Science 351:503-7
Tang, Xiao Xiao; Ostedgaard, Lynda S; Hoegger, Mark J et al. (2016) Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J Clin Invest 126:879-91
Abou Alaiwa, Mahmoud H; Launspach, Janice L; Sheets, Kelsey A et al. (2016) Repurposing tromethamine as inhaled therapy to treat CF airway disease. JCI Insight 1:
Meyerholz, David K; Lambertz, Allyn M; McCray Jr, Paul B (2016) Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. Am J Pathol 186:78-86
Hornick, Andrew L; Li, Ni; Oakland, Mayumi et al. (2016) Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors. Hum Gene Ther 27:354-62
Meyerholz, David K (2016) Lessons learned from the cystic fibrosis pig. Theriogenology 86:427-32

Showing the most recent 10 out of 90 publications