Disruption of vocal fold epithelial homeostasis by injury and papillomavirus infection

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Recurrent respiratory papillomatosis (RRP) is a highly morbid laryngeal disease caused by low-risk human papillomavirus (HPV) types 6 and 11. RRP is characterized by quickly growing epithelial lesions that impair voice function. Hoarseness is the most common symptom, resulting in significant communication impairment in patients with RRP. Available HPV vaccines are preventive only, have low uptakes in the US and globally, and are given well after RRP arises in children. RRP management involves repeated laryngeal surgery, which can scar vocal folds and permanently worsen the voice. Risk factors for RRP onset are poorly understood. Most HPV infections are transient: cleared by the immune system without establishing chronic infection or clinical disease. The goal of this proposal is to better understand how PV establishes vocal fold infections that lead to RRP in immunocompetent individuals. One potential avenue is injury. Vocal folds are subject to injury from multiple mechanical and environmental exposures. PV is thought to enter tissue via a microwound. However, in the novel in vivo laryngeal mouse papillomavirus (MmuPV1) infection model, laryngeal injury is not required for chronic laryngeal PV infection and disease in the absence of an immune system. This means that uninjured vocal fold epithelium permits PV entry. In contrast, in immunocompetent mice, MmuPV1 can only cause vocal fold disease when epithelium is injured, which indicates that there must be other factors in PV-induced vocal fold disease establishment besides initial viral entry into epithelium. This proposal will test the overarching hypothesis that vocal fold injury not only physically facilitates PV entry into epithelium, it also disrupts epithelial homeostasis and immunity and facilitates increased PV gene expression, such that PV overpowers the ability of the immune system to control the infection. Aim 1 will use the MmuPV1 laryngeal infection model to define the extent to which injury enhances PV-induced vocal fold disease in immunocompetent individuals, including the effect of injury on vocal fold disease in a low-risk HPV milieu that better recapitulates RRP. Aim 2 will use novel in vivo and in vitro platforms to define the mechanisms by which injury enhances PV-induced vocal fold disease throughout each phase of the viral life cycle. By better defining how low-risk HPV exploits vocal fold injury to establish infections that lead to RRP in immunocompetent individuals, completion of the specific aims will have a significant and sustained impact on laryngology and PV biology. The career development plan includes advanced virology and molecular biology techniques. Together with clinical training and an extensive background in laryngeal biology, these new skills will place the candidate in a strong position to work independently toward her long-term goal to become a clinician-scientist faculty member in academia with a translational research program that uses well-validated preclinical models to improve mechanistic understanding of RRP. The University of Wisconsin-Madison is an ideal environment for the K99 phase evidenced by long-established and active communities and mentors in virology and laryngeal biology.