The Gram-negative bacterium Bordetella pertussis is a human restricted pathogen that causes severe respiratory infection and the disease known as whooping cough or pertussis. The recent rise in B. pertussis infections and the disease in the USA and other high income countries, along with waning immunity to current commercial pertussis vaccines necessitate research on understanding the pathogenic mechanisms employed by this bacterium. Our overall hypothesis is that the formation of biofilms is essential for persistent colonization of the respiratory tract and pathogenesis of B. pertussis. Control of biofilm development in the largely animal pathogen B. bronchiseptica is mediated by BpsR, a highly conserved transcriptional regulator. Additionally, BpsR dually activates or represses the expression of a large number of genes which have roles in virulence, transcriptional regulation, metabolic and other cellular processes. Nothing is known about the role of BpsR in B. pertussis. Functional studies of BpsR in B. pertussis have been hindered by the inability to construct a mutant strain lacking the bpsR gene. This suggests that bpsR is an essential gene in B. pertussis. We hypothesize that by regulating the expression of genes involved in essential metabolic pathways, pathogenesis and biofilm formation, BpsR controls the ability of B. pertussis to survive in the respiratory tract.
In Specific Aim 1, we will utilize a tetracycline dependent conditional silencing system to examine its role in laboratory growth, gene expression and biofilm development.
In Specific Aim 2, these studies will be extended to an intranasal mouse model of B. pertussis infection and biofilm development to identify its role in colonization of and formation of biofilms on respiratory organs.
This proposal is designed to discover the function of regulator BpsR in Bordetella pertussis. B. pertussis causes the disease whooping cough or pertussis. We have identified BpsR as a global regulator of gene expression and as being essential for laboratory growth. This research will stimulate the development of targeted drugs to interfere with BpsR expression and activity thereby preventing disease reemergence and continued circulation of B. pertussis.
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