M. catarrhalis pili: Role in Colonization-infection

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DESCRIPTION (provided by applicant): Moraxella catarrhalis is a Gram-negative human pathogen, which predominantly causes middle ear infections and sinusitis in infants and children, and lower respiratory tract infections in adults. This organism is the third leading cause of otitis media and it is estimated that approximately 50% of children will become colonized by this bacterium in the first 6 months of life. Recurrent acute otitis media infections have also become prevalent resulting in potential hearing loss and subsequent developmental and learning problems as these children reach school age. Middle ear infections are very common and it is estimated that 80% of children under the age of 3 will experience at least one episode. There are also significant health care costs associated with treatment for otitis media and it has been determined that M. catarrhalis is responsible for approximately 3 to 4 million physician office visits annually. This estimate is considered conservative now that over 90% of M. catarrhalis clinical isolates produce beta-lactamase. Together, these data have stimulated research efforts aimed at identifying specific virulence factors involved in colonization and infection. At the otitis media workshop sponsored by the NIDCD in 2000 the panel emphasized the need for more research efforts dedicated to the identification of bacterial colonization factors and the identification of new vaccine and treatment targets. In this proposal we describe the identification and characterization of the genes that are involved in the biosynthesis and assembly of M. catarrhalis pili. To date these structures have been totally ignored as putative colonization factors. The data we present in this application demonstrate that we have identified multiple M. catarrhalis genes with homology to genes of the type IV pili (TFP) systems described for other important gram-negative human pathogens. Our studies show that pili expression is conserved both at the genetic and phenotypic levels. We hypothesize that pili expression is an essential component in the early stages of colonization and thus these structures may be important targets for the human immune response. The specific aims of this proposal are: 1) Isolate and characterize the genes involved in the biosynthesis, assembly, extrusion and retraction of M. catarrhalis pili. 2) Evaluate the function of M. catarrhalis pili in colonization and pathogenesis and characterize the antibody response to PilA and PilQ.