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.

Public Health Relevance

Recurrent respiratory papillomatosis, caused by papillomavirus infection in the larynx, has devastating effects on voice, communication, breathing, and quality of life, but is understudied compared to other papillomavirus- associated diseases. The goal of this proposal is to investigate the effect of vocal fold injury on papillomavirus infection and the effects of infection on vocal fold epithelium as disease progresses. Clarifying the interplay of tissue injury and papillomavirus infection in vocal folds will provide novel insight into the role of natural threats to vocal fold tissue integrity such as intubation, excess voice use, and environmental exposures in pathogenesis of recurrent respiratory papillomatosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
3F31DC018184-02S1
Application #
10366614
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Rivera-Rentas, Alberto L
Project Start
2019-09-01
Project End
2021-11-30
Budget Start
2020-09-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715