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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL091842-07
Application #
8737937
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Reznikov, Leah R; Meyerholz, David K; Kuan, Shin-Ping et al. (2018) Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways. Lung 196:219-229
Meyerholz, David K; Sieren, Jessica C; Beck, Amanda P et al. (2018) Approaches to Evaluate Lung Inflammation in Translational Research. Vet Pathol 55:42-52
Meyerholz, David K; Stoltz, David A; Gansemer, Nick D et al. (2018) Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs. Lab Invest 98:825-838
Gray, Robert D; Hardisty, Gareth; Regan, Kate H et al. (2018) Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax 73:134-144
Meyerholz, David K; Beck, Amanda P; Goeken, J Adam et al. (2018) Glycogen depletion can increase the specificity of mucin detection in airway tissues. BMC Res Notes 11:763
Meyerholz, David K; Reznikov, Leah R (2017) Simple and reproducible approaches for the collection of select porcine ganglia. J Neurosci Methods 289:93-98
Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher et al. (2017) Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. Am J Respir Crit Care Med 195:1617-1628
Paemka, Lily; McCullagh, Brian N; Abou Alaiwa, Mahmoud H et al. (2017) Monocyte derived macrophages from CF pigs exhibit increased inflammatory responses at birth. J Cyst Fibros 16:471-474
Meyerholz, David K; Ofori-Amanfo, Georgina K; Leidinger, Mariah R et al. (2017) Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models. J Histochem Cytochem 65:607-618
Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J et al. (2017) Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs. Crit Care Med 45:e1240-e1246

Showing the most recent 10 out of 110 publications