Project Grant F31HL186594

DEFINING THE ROLES OF MUCUS AND PSEUDOMONAS AERUGINOSA EPS IN SENSORY NEURON EVASION IN CF LUNGS - PROJECT SUMMARY- ABSTRACT CYSTIC FIBROSIS (CF) IS A LIFE-LIMITING AUTOSOMAL RECESSIVE DISORDER THAT IS CAUSED BY A MUTATION IN THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) GENE. THIS DYSFUNCTION RESULTS IN THE ACCUMULATION OF PULMONARY MUCUS AND A LOSS OF MUCOCILIARY FUNCTION. CURRENT THERAPIES, INCLUDING CFTR MODULATORS IMPROVE LUNG FUNCTION, BUT THEY DO NOT ADDRESS THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN PEOPLE WITH CF: PSEUDOMONAS AERUGINOSA INFECTIONS. AN UNDEREXPLORED AREA OF P. AERUGINOSA IMMUNE EVASION MAY INVOLVE INTERACTIONS WITH SENSORY NEURONS. EARLIER FINDINGS SHOWED THAT VAGAL TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1) AFFERENT NEURONS RELEASE SPECIFIC NEUROPEPTIDES TO SUPPRESS NEUTROPHILS AND T CELLS, THEREBY IMPROVING SURVIVAL IN RESPONSE TO STAPHYLOCOCCUS AUREUS INFECTION. IMPORTANTLY, A RECENT STUDY FOUND THAT EXOPOLYSACCHARIDE (EPS) PRODUCED BY P. AERUGINOSA ENABLED BACTERIA TO EVADE INITIATION OF A LUNG-BRAIN SENSORY NEURONAL RESPONSE BY OBSTRUCTING LIPOPOLYSACCHARIDE (LPS) BINDING TO TOLL-LIKE RECEPTOR 4 (TLR4), RESULTING IN REDUCED SICKNESS BEHAVIOR IN C57BL/6-WT MICE. WE THEREFORE HYPOTHESIZE THAT MUCUS AND P. AERUGINOSA EPS OBSTRUCT THE ABILITY OF SENSORY NEURONS TO DETECT AND/OR DISRUPT NEUROPEPTIDE RELEASE, LEADING TO AN INEFFECTIVE IMMUNE RESPONSE. HERE WE WILL UTILIZE SCNN1B-TG MICE, WHICH OVEREXPRESS THE ENAC SODIUM CHANNEL AND MIMIC CF BY INDUCING MUCUS HYPERACCUMULATION COMBINED WITH AN ESTABLISHED MODEL OF SENSORY NEURON ABLATION WITH RESINIFERATOXIN (RTX). AIM 1 WILL COMPARE THE EFFECTS OF RTX AND MUCOLYTIC TREATMENT DURING AN ACUTE P. AERUGINOSA-WT STRAIN AND A P. AERUGINOSA EPS DELETION STRAIN TO DETERMINE WHETHER MUCUS AND/OR EPS ACTS SYNERGISTICALLY OR ADDITIVELY IN THE HINDRANCE OF THE INNATE NEUROIMMUNE CROSSTALK. IN AIM 2, WE WILL INVESTIGATE THE ROLE OF MUCUS AND EPS IN NEURON DETECTION AND HUMORAL IMMUNE RESPONSE DURING A PRE-EXPOSURE P. AERUGINOSA INFECTION MODEL. THESE EXPERIMENTS WILL ELUCIDATE A NOVEL MECHANISM OF SENSORY NEURON EVASION BY P. AERUGINOSA IN CF. THESE FINDINGS MAY REVEAL NEW TARGETS FOR NEUROIMMUNE INTERACTIONS TO ENHANCE BACTERIAL CLEARANCE IN CF.