Specialty Areas: Innate Immune Factors in CF and COPD Patients; Development of Gene Therapy for Viral Infection
To better understand how common respiratory viruses infect the human lung and how cell-type tropism and innate immune factors influence the pathophysiological consequences of viral infection especially in individuals with underlying lung diseases such as cystic fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD).The Pickles laboratory is located in the Cystic Fibrosis/Pulmonary Research and Treatment Center in the Thurston-Bowles building at UNC. We study how human respiratory virus pathogens infect the human lung with focus on how viruses interact with lung cells and how virus infection alters the normal functions of the lung. Our research has three major goals related to CF lung disease.
- To exploit the efficient mechanisms that respiratory viruses have evolved to infect respiratory epithelium for the development of strategies to deliver therapeutic transgenes to human airways. This is particularly relevant to the genetic delivery of CFTR to the airways of CF patients.
- To understand the role of ciliated airway epithelial cells in respiratory virus infection. These cells are predominant in the airways of humans and are often the target of common respiratory virus infection. We study the innate defense mechanisms provided by ciliated cells both at the level of mechanical innate defense (Mucociliary transport) and chemical innate defense (inflammatory mediators). Understanding the role of ciliated cells in these innate mechanisms is important for virus pathogenesis, gene therapy strategies and vaccine design.
Currently, we focus on three common respiratory viral pathogens: respiratory syncytial virus (RSV); the parainfluenza viruses (PIV) and influenza viruses (IFV) since these viruses are amongst the most common cause of viral infections in infants and children. These viruses are also a concern in individuals with compromised lungs, e.g., CF patients, and those who have undergone lung transplantation. However, we have enjoyed many successful collaborations with other groups who study coronaviruses (e.g., SARS-CoV) and rhinoviruses.
Given the high complexity of the airway epithelium it is clear that characteristics of virus-host cell interactions determined with common laboratory cell-lines need to be interpreted with caution. In addition, most human respiratory viruses have limited species tropism with human being predominant (sometimes only) host. Therefore, human airway epithelium models derived from human primary airway epithelial cells obtained from CF or non-CF patients have provided novel culture models that allow new insights into the infection characteristics of human respiratory viruses. Isolated airway epithelial cells grown over a period of 1-2 months at an air-liquid interface result in the generation of a pseudostratified, mucociliary airway epithelium that displays similar morphologic and phenotypic characteristics of the in vivo human cartilaginous airway epithelium. Recent studies have revealed that this model system recapitulates the phenotypic differences that occur between CF and non-CF airway epithelium and important characteristics of respiratory virus-host cell interactions.
- Kesimer M, Ehre C, Burns KA, Davis CW, Sheehan JK, Pickles RJ. Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways. Mucosal Immunol. 2013 Mar;6(2):379-92. doi: 10.1038/mi.2012.81. Epub 2012 Aug 29. PubMed PMID: 22929560; PubMed Central PMCID: PMC3637662.
- Ehre C, Worthington EN, Liesman RM, Grubb BR, Barbier D, O’Neal WK, Sallenave JM, Pickles RJ, Boucher RC. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16528-33. doi: 10.1073/pnas.1206552109. Epub 2012 Sep 24. Erratum in: Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5753. PubMed PMID: 23012413; PubMed Central PMCID: PMC3478656.
- Nguyen Y, Procario MC, Ashley SL, O’Neal WK, Pickles RJ, Weinberg JB. Limited effects of Muc1 deficiency on mouse adenovirus type 1 respiratory infection. Virus Res. 2011 Sep;160(1-2):351-9. doi: 10.1016/j.virusres.2011.07.012. Epub 2011 Jul 26. PubMed PMID: 21816184; PubMed Central PMCID: PMC3163747.
- Okada SF, Zhang L, Kreda SM, Abdullah LH, Davis CW, Pickles RJ, Lazarowski ER, Boucher RC. Coupled nucleotide and mucin hypersecretion from goblet-cell metaplastic human airway epithelium. Am J Respir Cell Mol Biol. 2011 Aug;45(2):253-60. doi: 10.1165/rcmb.2010-0253OC. Epub 2010 Oct 8. PubMed PMID: 20935191; PubMed Central PMCID: PMC3175555.
- Johnson JS, Gentzsch M, Zhang L, Ribeiro CM, Kantor B, Kafri T, Pickles RJ, Samulski RJ. AAV exploits subcellular stress associated with inflammation, endoplasmic reticulum expansion, and misfolded proteins in models of cystic fibrosis. PLoS Pathog. 2011 May;7(5):e1002053. doi: 10.1371/journal.ppat.1002053. Epub 2011 May 19. PubMed PMID: 21625534; PubMed Central PMCID: PMC3098238.