Moraxella catarrhalis, a human mucosal pathogen, is a prominent cause of otitis media in young children and lower respiratory tract infections in adults with COPD. The significant financial burden on the health care system in this country, has stimulated research studies aimed at identifying possible vaccine components expressed on the bacterial surface. Recent studies have focused on components of the bacterial outer membrane, as these structures would most likely be available for interaction with the host immune response. However, it is clear that little is known about the virulence factors and the host immune response to M. catarrhalis. One prominent bacterial surface component, implicated as a potential virulence factor, is the lipooligosaccharide (LOS). Structural studies have shown that this major glycolipid is relatively conserved among clinical isolates obtained from adults. There have been three LOS serotypes reported using polyclonal rabbit sera for detection. In addition, a comparison of M. catarrhalis LOS has shown that this structure has oligosaccharide epitopes which share homology with the LOS of 9other important Gram-negative human pathogens, including Neisseria meningitis, Neisseria gonorrhea and Haemophilus influenzae. The LOPS epitopes shared by M. catarrhalis and these other important pathogens have been implicated as potential virulence factors involved in various mechanisms of pathogenesis including adherence and invasion of mucosal cells, serum resistance and resistance to opsonophagocytosis. In addition, recent studies have shown that antibodies to M. catarrhalis LOS elicit bactericidal activity, suggesting that this molecule may be an important component of a multifactorial vaccine. Despite these data, there is very little known about the role of M. catarrhalis LOS in colonization of infection, and there are no studies reported which characterize the genes and gene products of this important bacterial component. In this proposal, we will clone and sequence genes involved in the biosynthesis and assembly of LOS and we will construct specific isogenic mutants in these genes. These LOS mutants will be evaluated in various biologic assays to begin to understand the role of this molecule in pathogenesis. Also, we will perform a detailed analysis of the human antibody response to LOS in both children and adults which will provide insight into the host-pathogen relationship. The data obtained from these studies will provide critical information to our understanding of the steps involved in the pathogenesis of M. catarrhalis infections which will lead to new insight into strategies designed to prevent disease.
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