Respiratory virologist

LIQUN ZHANG, PHD

*** ********** ******, ****** ****, NC 27517 ■ 919-***-**** ■ *******@*****.***

Accomplished researcher in respiratory virology and vaccine development with a record of high-impact publications in leading scientific journals. Broad experience and knowledge in respiratory epithelial cell biology with masterful technical skills. Extensive expertise in respiratory viruses (e.g., RSV, PIV3, PIV5, influenza virus, and AAV) and vaccine studies. Proven success in applying innovative approaches to diverse challenges. Experienced manager of complex research projects and high-performance research teams.

ACHIEVEMENTS

Evaluated attenuation phenotypes of vaccine candidates in human airway epithelium

Developed the most efficient gene transfer vectors targeting human airways

Therapeutically corrected the bioelectric defects of cystic fibrosis lung disease by gene transfer

Generated novel adeno-associated virus (AAV) variants with improved airway tropism

Discovered key mechanisms for virus-mediated cytopathology

PROFESSIONAL EXPERIENCE

University of North Carolina at Chapel Hill 2002 - present

CF/Pulmonary Research & Treatment Center

Research Scientist

Project: To investigate the mechanisms of infection of common respiratory viruses including respiratory syncytial virus (RSV), parainfluenza virus (PIV) type 3, PIV5, Sendai virus, and influenza virus.

Outcome: Identified the ciliated epithelial cells as the main target cell type for RSV, PIV3, and PIV5 infection and replication. Discovered the regulated epithelial cell shedding as the main mechanism for virus-mediated cytopathology. Performed preclinical testing of anti-viral drugs/compounds. Assessed the attenuation phenotypes of viral vaccine candidates. These results improved the understanding of viral infections in human airways and built the foundation for treating these viral diseases.

Project: To develop recombinant viral vectors for gene delivery to human respiratory airways.

Outcome: Generated replication-competent viral vectors (based on RSV and PIV3) expressing GFP and/or CFTR genes with reverse genetics and demonstrated for the first time that these vectors transduced intact human airway epithelium at an efficiency sufficient to fully correct the bioelectric defect in CF epithelium. A biomarker for non-invasive quantification of gene transfer in the airways was developed and proved to be sensitive and quantitative in animal models (e.g., non-human primates). These studies bring us a step closer to the reality of gene-based therapy for CF and other airway diseases.

Project: To improve adenovirus-associated virus (AAV) vectors for gene transfer to airways (in collaboration with Dr. R. Jude Samulski, UNC Gene Therapy Center).

Outcome: Generated and perfected the state-of-the-art 3D model of human airway epithelia under air-liquid interface (ALI). Performed in vitro evolution with AAV DNA-shuffling library and generated novel AAV variants with improved airway tropism than any known AAV serotypes. The novel AAV variants were further validated in vivo in mouse noses.

Project: To identify new viruses in diseased human lungs.

Outcome: (Underway) Using a metagenomic approach, the goal is to assess the whole viral milieu in the lungs of CF, chronic obstructive pulmonary disease (COPD), and other patients, to identify new pathogenic viruses infecting human lungs.

Accomplishments:

Developed high-impact research projects and obtained grant funding from NIH and CF Foundation (grant writing, budget preparation, animal and human subject research compliance). Managed research projects and laboratory personnel (study design, troubleshooting, reporting, supervision, and performance evaluations). Established long-term collaborations with renowned world experts in respiratory virology.

EDUCATION AND TRAINING

Postdoc University of North Carolina at Chapel Hill, North Carolina

Gene therapy for cystic fibrosis

Supervisors: Richard C. Boucher, MD & Raymond J. Pickles, PhD

PhD University of Maryland at Baltimore, Baltimore, Maryland

Major: Human genetics

Adviser: Rong-Fong Shen, PhD

BS Tsinghua University, Beijing, China

Major: Biological Sciences and Biotechnology

PROFESSIONAL AFFILIATIONS

American Society for Microbiology

American Society of Gene & Cell Therapy

North American Cystic Fibrosis Association

PUBLICATIONS

(peer-reviewed papers)

Zhang L*, Collins PL, Lamb RA, Pickles RJ. Comparison of differing cytopathic effects in human airway epithelium of parainfluenza virus 5 (W3A), parainfluenza virus type 3, and respiratory syncytial virus. Virology. 2011 Dec 5;421(1):67-77. Epub 2011 Oct 8. PMID: 21986028; PMCID: PMC3208758. (*corresponding author)

Li W, Zhang L, Wu Z, Pickles RJ, Samulski RJ. AAV-6 mediated efficient transduction of mouse lower airways. Virology. 2011 Sep 1;417(2):327-33. Epub 2011 Jul 14. PMID: 21752418; PMCID: PMC3163804.

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. Epub 2011 May 19. PMID: 21625534; PMCID: PMC3098238.

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. Epub 2010 Oct 8. PMID: 20935191; PMCID: PMC3175555.

Zhang L*, Limberis M, Thompson C, Antunes MB, Luongo C, Wilson JM, Collins PL, Pickles RJ. α-Fetoprotein gene delivery to the nasal epithelium of nonhuman primates by human parainfluenza viral vectors. Hum Gene Ther. 2010 Dec;21(12):1657-64. Epub 2010 Nov 3. PMID: 20735256; PMCID: PMC2999572. (*corresponding author)

Feature Cover in Human Gene Therapy, December 2010, Volume 21, Number 12.

Kwilas AR, Yednak MA, Zhang L, Liesman R, Collins PL, Pickles RJ, Peeples ME. Respiratory syncytial virus engineered to express the cystic fibrosis transmembrane conductance regulator corrects the bioelectric phenotype of human cystic fibrosis airway epithelium in vitro. J Virol. 2010 Aug;84(15):7770-81. Epub 2010 May 26. PMID: 20504917; PMCID: PMC2897634.

Feature Cover in Journal of Virology, November 2010, Volume 84, Issue 21.

Li W, Zhang L, Johnson JS, Wu Z, Grieger JC, Xiao P-J, Drouin LM, Agbandje-McKenna M, Pickles RJ, and Samulski RJ. Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol Ther. 2009 Dec;17(12):2067-77. Epub 2009 Jul 14. PMID: 19603002; PMCID: PMC2801879.

Kwilas S, Liesman RM, Zhang L, Walsh E, Pickles RJ, and Peeples ME. Respiratory syncytial virus grown in vero cells contains a truncated attachment protein that alters its infectivity and dependence on glycosaminoglycans. J Virol. 2009 Oct;83(20):10710-8. Epub 2009 Aug 5. PMID: 19656891; PMCID: PMC2753119.

SPOTLIGHT: Featured article of significant interest selected by the editors.

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. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 2009 Jul;7(7):e1000155. Epub 2009 Jul 21. PMID: 19621064; PMCID: PMC2705187.

SYNOPSIS: Meadows R. Engineered common cold virus helps cultured cystic fibrosis tissues clear mucus. PLoS Biol. 2009 Jul;7(7):e1000155. PubMed PMID: 20076750; PMCID: PMC2704862.

Feature Cover in PLoS Biology July 2009, Issue 7(7).

Limberis MP, Vandenberghe LH, Zhang L, Pickles RJ, and Wilson JM. Transduction efficiencies of novel AAV vectors in mouse airway epithelium In vivo and human ciliated airway epithelium in vitro. Mol Ther. 2009 Feb;17(2):294-301. Epub 2008 Dec 9. PMID: 19066597; PMCID: PMC2835069.

Bukreyev A, Marzi A, Feldmann F, Zhang L, Yang L, Ward JM, Dorward DW, Pickles RJ, Murphy BR, Feldmann H, Collins PL. Chimeric human parainfluenza virus bearing the Ebola virus glycoprotein as the sole surface protein is immunogenic and highly protective against Ebola virus challenge. Virology. 2009 Jan 20;383(2):348-61. Epub 2008 Nov 17. PMID: 19010509; PMCID: PMC2649782.

Tarran R, Button B, Picher M, Paradiso AM, Ribeiro CM, Lazarowski ER, Zhang L, Collins PL, Pickles RJ, Fredberg JJ, and Boucher RC. Normal and cystic fibrosis airway surface liquid homeostasis: The effects of phasic shear stress and viral infections. J Biol Chem. 2005 Oct 21;280(42):35751-9. Epub 2005 Aug 8. PMID: 16087672; PMCID: PMC2924153.

Das S, Palmer OP, Leight WD, Poston AN, Zhang L, Pickles RJ, Randell SH, Buchman CA. Cytokine amplification by respiratory syncytial virus infection in human nasal epithelial cells. Laryngoscope. 2005 May;115(5):764-8. Erratum in: Laryngoscope. 2005 Nov;115(11):2076. PMID: 15867636.

Zhang L, Bukreyev A, Thompson CI, Watson B, Peeples ME, Collins PL, and Pickles RJ. Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium. J Virol. 2005 Jan;79(2):1113-24. PMID: 15613339; PMCID: PMC538579.

Mellow TE, Murphy PC, Carson JL, Noah TL, Zhang L, and Pickles RJ. The effect of respiratory syncytial virus on chemokine release by differentiated airway epithelium. Exp Lung Res. 2004 Jan-Feb;30(1):43-57. PMID: 14967603.

Zhang L*, Peeples ME, Boucher RC, Collins PL, and Pickles RJ. Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious Cytopathology. J Virol. 2002 Jun;76(11):5654-66. PMID: 11991994; PMCID: PMC137037. (*corresponding author)

Zhang L, Xiao H, Schultz RA, and Shen R-F. Genomic organization, chromosomal localization, and expression of the murine thromboxane synthase gene (Tbxas1). Genomics. 1997 Nov 1;45(3):519-28. PMID: 9367676.

Shen RF, Baek SJ, Lee KD, Zhang L, Fleischer T. Genomic organization and regulation of the human thromboxane synthase gene. Adv Prostaglandin Thromboxane Leukot Res. 1995;23:137-9. PMID: 7732819.

Shen R-F, Zhang L, Baek SJ, Tai H-H, and Lee K-D. The porcine thromboxane synthase-encoding cDNA: sequence, mRNA expression and enzyme production in Sf9 insect cells. Gene. 1994 Mar 25;140(2):261-5. PMID: 8144035.

Zhang L, Chase MB, and Shen R-F. Molecular cloning and expression of murine thromboxane synthase. Biochem Biophys Res Commun. 1993 Jul 30;194(2):741-8. PMID: 7688225.

ORAL PRESENTATIONS

The IX International Symposium on Respiratory Viral Infections, Hong Kong.

Title: Are we using the right cells? Studies of respiratory viruses with an in vitro model of well-differentiated airway epithelia.

The VII International Symposium on Respiratory Viral Infections, Curacao, Netherlands Antilles.

Title: Exploiting respiratory virus tropism for ciliated epithelial cells for the development of gene transfer vectors as biological tools and potentially therapeutic strategies.

The American Society of Gene Therapy 7th Annual Meeting, Minneapolis, MN.

Title: Parainfluenza virus-mediated delivery of CFTR to ciliated cells corrects the CF bioelectrical chloride secretory defect and restores the regulation of airway surface liquid depth and mucus transport to cyctic fibrosis airway epithelium.

The 16th Annual North American Cystic Fibrosis Conference, New Orleans, LA.

Title: Recombinant human parainfluenza virus type 3 (hPIV3) infects human ciliated airway epithelium via the apical surface.

The 15th Annual North American Cystic Fibrosis Conference, Orlando, FL.

Title: Respiratory syncytial virus (RSV) infects ciliated cells of airway epithelium via the lumenal membrane.

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