Impact of mucin fermenting microbes on the virulence of Pseudomonas aeruginosa in chronic rhinosinusitis

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Title: Impact of mucin fermenting microbes on the virulence of Pseudomonas aeruginosa in chronic rhinosinusitis Project Summary/Abstract Chronic rhinosinusitis (CRS) is a chronic airway disease defined as persistent inflammation and infection of the nasal and sinus mucosa. Microbes affect human health through interspecies interactions, with a broad spectrum of outcomes - some beneficial, others pathogenic. Disruption of the stable microbiota in the sinuses and pathogen overgrowth can lead to benign microbial communities becoming pro-inflammatory and invasive. Pseudomonas aeruginosa is an opportunistic, gram-negative bacterial species associated with severe, recalcitrant CRS; CRS patients with P. aeruginosa correlate with poor symptom resolution and worse clinical outcomes, leading to complications, such as orbital cellulitis and brain abscess, even in non- immunocompromised individuals. Thus, identifying the mechanisms underlying the virulence of P. aeruginosa in CRS progression is critical to developing new treatment strategies. Our aims are designed to test a hypothesis that mucin-fermenting microbes promote the microbial virulence of P. aeruginosa, leading to the progression of recalcitrant CRS. (1) To evaluate whether enhanced P. aeruginosa virulence and CRS progression in vivo rely on mucin fermentation by B. fragilis. We expect CRS rabbits inoculated with wild-type P. aeruginosa and wild-type B. fragilis to exhibit the most severe CRS phenotype with marked tissue invasion and virulence-associated gene/protein markers. (2) To determine how mucin-fermenting microbes modulate P. aeruginosa tissue invasion and antibiotic resistance in vitro. We expect to identify the critical actors in modulating antibiotic resistance and invasion in human tissue. We expect this proposal to answer fundamental questions regarding P. aeruginosa virulence in recalcitrant, destructive CRS, which, in turn, can lead to develop new, effective treatment strategies for a disease that exacts an enormous healthcare burden. The proposed experiments will also shed light on how interactions with mucin-fermenting microbes influence other airway diseases associated with P. aeruginosa, such as malignant otitis externa, cystic fibrosis, and chronic obstructive pulmonary disease.