7106 Marsico Hall
My laboratory, located in the Cystic Fibrosis/Pulmonary Research and Treatment Center in the Thurston-Bowles building at UNC, is interested in respiratory virus infection of the lung. This research has two major goals:
- To develop a better understanding of how common respiratory viruses infect the 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).
- To exploit the mechanisms that respiratory viruses have evolved to infect respiratory epithelium for the development of strategies to deliver therapeutic transgenes to the airways of patients with diseases such as cystic fibrosis.
Currently, we are focused on the following common respiratory viral pathogens: influenza viruses (human and avian); respiratory syncytial virus (RSV); and parainfluenza viruses (PIV) since these viruses are amongst the most common cause of viral infections in infants and children and have high incidence of morbidity in patients with chronic lung disease.
We use in vitro and in vivo models to test factors that influence the extent and duration of virus infection and what inflammatory consequences occur after infection of the epithelial cells of the lung. We are especially interested in the altered environment of the inflamed lung and how this environment may affect the infection and consequences of infection by respiratory viruses.
Models of Human Airway Epithelium to Study Virus-Host Cell Interactions
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 undergoing lung transplantation 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 (Figure 1). 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.
Li W, Zhang L, Wu Z, Pickles RJ, Samulski RJ (2011). AAV-6 mediated efficient transduction of mouse lower airways. Virology. 417(2):327-33.
Zhang L, Limberis MP, Thompson C, Antunes MB, Luongo C, Wilson JM, Collins PL, Pickles RJ (2010). α-Fetoprotein gene delivery to the nasal epithelium of nonhuman primates by human parainfluenza viral vectors. Hum Gene Ther. 21(12):1657-64.
Pyrc K, Sims AC, Dijkman R, Jebbink M, Long C, Deming D, Donaldson E, Vabret A, Baric R, van der Hoek L, Pickles R (2010). Culturing the unculturable: human coronavirus HKU1 infects, replicates, and produces progeny virions in human ciliated airway epithelial cell cultures. J Virol. 84(21):11255-63.
Schaap-Nutt A, Scull MA, Schmidt AC, Murphy BR, Pickles RJ (2010). Growth restriction of an experimental live attenuated human parainfluenza virus type 2 vaccine in human ciliated airway epithelium in vitro parallels attenuation in African green monkeys. Vaccine. 28(15):2788-98.
Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, Skiadopoulos MH, Dang YL, Vogel LN, McKay T, Mengos A, Boucher RC, Collins PL, Pickles RJ (2009). CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 7(7):e1000155.
Scull MA, Gillim-Ross L, Santos C, Roberts KL, Bordonali E, Subbarao K, Barclay WS, Pickles RJ (2009). Avian Influenza virus glycoproteins restrict virus replication and spread through human airway epithelium at temperatures of the proximal airways. PLoS Pathog. 5(5):e1000424.
Bartlett EJ, Hennessey M, Skiadopoulos MH, Schmidt AC, Collins PL, Murphy BR, Pickles RJ (2008). Role of interferon in the replication of human parainfluenza virus type 1 wild type and mutant viruses in human ciliated airway epithelium. J Virol. 82(16):8059-70.
Sims AC, Burkett SE, Yount B, Pickles RJ (2008). SARS-CoV replication and pathogenesis in an in vitro model of the human conducting airway epithelium. Virus Res. 133(1):33-44.
Sheehan JK, Kesimer M, Pickles R (2006). Innate immunity and mucus structure and function. Novartis Found Symp. 279:155-66; discussion 167-9, 216-9. Review.
Sims AC, Yount B, Burkett SE, Baric RS, Pickles RJ (2006). SARS CoV replication and pathogenesis in human airway epithelial cultures. Adv Exp Med Biol. 581:535-8.
Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006). Infection of human airway epithelium by human and avian strains of influenza a virus. J Virol. 80(16):8060-8.
Sims AC, Baric RS, Yount B, Burkett SE, Collins PL, Pickles RJ. 2005. Severe acute Respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs. J Virol. 2005;79(24):15511-24.
Tarran R , Button B, Picher M, Paradiso AM, Ribeiro CM, Lazarowski ER, Zhang L , Collins PL, Pickles RJ, Fredberg JJ, Boucher RC. 2005. Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J Biol Chem. 21;280(42):35751-9.
Das S, Palmer OP, Leight WD, Surowitz JB, Pickles RJ, Randell SH, Buchmanb CA. 2005. Cytokine amplification by respiratory syncytial virus infection in human nasal epithelial cells. Laryngoscope. 115: 764-768.
Zhang L, Bukreyev A, Thompson CI, Watson B, Peeples ME, Collins PL and Pickles RJ. 2005.Infection of Ciliated Cells by Human Parainfluenza Virus Type 3 in an In Vitro Model ofHuman Airway Epithelium. J. Virol. 79: 1113-1124.