Identification and characterization of a novel two-partner secretion system in Moraxella catarrhalis composed of MCHA1, MCHA2, and MCHB
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Moraxella catarrhalis has now emerged as an important human pathogen causing disease in both children and adults. M. catarrhalis is a predominant bacterial pathogen that causes otitis media in children. The acquisition of a new strain of M. catarrhalis is associated with an episode of exacerbation in adults with chronic obstructive pulmonary disease. The increasing socioeconomic cost of M. catarrhalis infection and the lack of a vaccine are major factors contributing to an increase in studies designed to understand the pathogenesis of this bacterium. In this thesis, we are reporting the identification of a novel virulence factor in M. catarrhalis called the M . c atarrhalis h emagglutinin-like (MCH) system. The MCH locus encodes for homologues of the two-partner secretion system (TPS), which the prototype is the filamentous hemagglutinin (FHA) of Bordetella pertussis. The purified FHA, a protective antigen, is a component of the acellular pertussis vaccine against whooping cough. Molecular characterization of the unique MCH locus determined that it is composed in the order of mchA1 ( tpsA ), mchB ( tpsB ), mchA2 ( tpsA ), where mchA1 is divergent. We hypothesized that the proteins encoded by these genes constitute a functional TPS system that would play a role in the pathogenesis of M. catarrhalis. The characterization of the MCH system has revealed that M. catarrhalis expresses a functional TPS system in which MchB is required for the extracellular transport of MchA1 and MchA2 to the cell surface and into the extracellular milieu. MchA1 and MchA2, which are 74% identical at the amino acid level and diverge only in the C-terminal regions, function independently in the adherence to NHBE cells. Our studies demonstrate that the MCH system is conserved among clinical isolates of M. catarrhalis. Comparative phylogenetic studies of twelve deduced MchA proteins demonstrated that they are closely related, the divergence being located at the C-termini. In addition, the MchB proteins from eleven clinical isolates of M. catarrhalis are highly conserved. This thesis work provides a foundation for further studies designed to better define the role and the function of the MCH system in the pathogenesis of M. catarrhalis mostly at the early steps of colonization.