Bordetella pertussis is an important pathogen of children and is also increasingly recognized in adults worldwide. Current pertussis vaccines do not prevent colonization, a prerequisite for eradication of disease. The understanding of the biology of the adherence interactions between Bordetella and human cells to be derived from this project can provide a rationale to improve this deficit in the vaccine. The substantial beneficial health impact of the diphtheria-pertussis-tetanus vaccine is achieved at the cost of the toxicity of the controversial pertussis component. This proposal examines the molecular mimicry used by B. pertussis to establish colonization of cilia and leukocytes with particular emphasis on the ability of B. pertussis adhesins to generate antibodies cross reactive with human cells. This aspect of the study addresses research needs identified by the Institute of Medicine to promote an understanding of the biologic basis of adverse events associated with pertussis disease and immunization. Pertussis toxin and filamentous hemagglutinin (FHA) are two antigenic bacterial surface proteins that act as adhesins. In the last 3 years, the minimum active domains of pertussis toxin and FHA that recognize cilia and macrophages, regions that are key to new subcomponent vaccines, have been defined. A profound structural and functional mimicry between these bacterial adhesins and the human adhesion molecules critical to leukocyte trafficking were then discovered. This renewal will dissect the domains of FHA that mimic the eukaryotic systems of complement fixation, coagulation and leukocyte trafficking. The molecular mechanism by which FHA co-opts these three natural host defense systems will be defined in detail. Finally, FHA-derived peptides from regions of mimicry will be assessed as possible therapeutic candidates to inhibit the undesirable triggering of the complement, coagulation and integrin systems of leukocyte recruitment during inflammation in bacterial infections. A further aim of this project relates to the implications of this molecular mimicry. Preliminary evidence strongly suggests that one domain of FHA mimics a new brain-specific receptor for leukocyte transmigration. This receptor will be cloned, sequenced and functionally characterized for its role in normal leukocyte trafficking to brain and its ability to participate in enhancing blood-brain barrier permeability.
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