Vocal fold epithelial barrier and proliferation in laryngeal papillomatosis

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ABSTRACT Recurrent respiratory papillomatosis (RRP) is a highly morbid upper airway disease caused by non-cancer- causing human papillomavirus (HPV) types 6 and 11. RRP is characterized by quickly growing clustered epithelial lesions in the larynx and upper airway. Although lesions are histologically benign, they cause voice disorders and can result in life-threatening airway obstruction, particularly in children. Repeated surgical excision of lesions required as often as every few months to maintain breathing can cause vocal fold scar and further impair voice function. Vaccination is preventive only. There is no cure for established HPV infection or for RRP. RRP research has been limited by the lack of a preclinical model. Papillomaviruses require layered epithelium to complete their life cycle. Clinically, RRP progression includes regression and recurrence of lesions. These aspects of disease are best captured using animal models, which have been limited since papillomaviruses are also species-specific. The recent discovery of murine papillomavirus MmuPV1 has created novel opportunities to model papillomavirus infection in genetically modifiable laboratory animals. However, there are no studies of MmuPV1 in vocal folds and/or larynx to date. The overall goal of this work is to define the interaction between vocal fold epithelial injury and papillomavirus infection using a novel murine model of laryngeal papillomatosis. Aim 1 will investigate the role of mechanical injury on MmuPV1 disease progression in murine larynx using longitudinal measures of disease burden and viral load, as well as localizing viral RNA and assembly of infectious particles within tissue at multiple timepoints during wound healing. In parallel, Aim 2 will characterize changes in epithelial morphology, barrier integrity, and cell proliferation and death induced by papillomavirus infection throughout wound healing. Our central hypothesis is that epithelial injury will facilitate viral infection, and that infection will disrupt normal epithelial integrity and cell turnover. By clarifying the role of vocal fold injury in onset of laryngeal papillomatosis and the initial effects of papillomatosis on vocal fold epithelium, completion of our specific aims will have a significant impact on laryngology and virology. This proposal will result in a novel preclinical model of RRP that will facilitate further study of disease persistence and recurrence, including the role of the immune system, and will ultimately be used to develop innovative prevention and treatment strategies for this intractable and devastating disease.