Genetics & Biology of M. catarrhalis LOS in Otitis Media

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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 b-lactamase. Together, these data have stimulated research efforts aimed at identifying specific virulence factors involved in colonization and infection. One prominent bacterial surface component implicated as a potential virulence factor, is the lipooligosaccharide (LOS). Structural studies show that M. catarrhalis LOS is similar to the LOS of other Gram-negative human pathogens, including Neisseris meningitidis, Neisseria gonorrhoeae and Haemophilus influenzae. More importantly, these common LOS structures shared by M. catarrhalis and these prominent human mucosal pathogens have been implicated as virulence factors. Although M. catarrhalis express these LOS epitopes, there have been minimal studies describing the role of LOS in pathogenesis. In addition, there is currently no information available regarding the assembly and expression of this major surface glycolipid. In this proposal we will perform a comprehensive analysis of the genetics and biology of M. catarrhalis LOS. These studies will be instrumental to our understanding of the role of LOS in the pathogenesis of otitis media and should provide insight into new strategies designed to prevent this disease. We will test our hypotheses by the following specific aims: (1) Isolate and characterize of the genes involved in the biosynthesis and assembly of M. catarrhalis LOS. (2)Perform biologic studies to define the role for M. catarrhalis LOS in otitis media.