Bordetella cell surface modification and pathogenesis

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The Gram-negative bacterium Bordetella pertussis is a human-restricted pathogen that causes severe respiratory infections and the disease whooping cough or pertussis. Despite high levels and widespread vaccination, there has been a world-wide rise in B. pertussis infections and pertussis. This resurgence is attributed to the ineffectiveness of the current acellular pertussis vaccines to control bacterial numbers in the nasopharynx, bacterial transmission and generation of shorter-lived immunity. How B. pertussis survives effectively in the respiratory tract and circulates in the community is poorly understood. In order to control the resurgence of pertussis, it is critical to discover new strategies and identify new pathogenesis-associated loci and factors. The draABCD locus identified in our laboratory promotes in vitro (i) the resistance to killing by anti-microbial peptides and proteins (AMPs); (ii) polymorphonuclear leukocytes and (iii) the formation of biofilms. We hypothesize that dra is critical for survival of B. pertussis in the mouse respiratory tract. In Specific aim 1, we will utilize well-established mouse models of intranasal infection to examine its role in colonization and biofilm formation in the respiratory tract organs. We will also test whether dra promotes adherence to respiratory epithelium by using epithelial cells lines and respiratory explants. The Dra proteins catalyze the addition of D-alanine in an outer membrane-associated protease-susceptible component. This mechanism of surface modification is distinct from the polysaccharide modification carried out by other known bacterial loci. The Dra-modified surface factor (DMF) is unknown. In Specific Aim 2, using fractionation techniques and mass spectrometry, we will identify the DMF. This work will uncover new virulence strategies that will inform on the reasons of the resurgence of pertussis. Studies of the dra locus and discovering the identity of the DMF will provide important biochemical and biological insights resulting in advanced understanding of surface alterations in B. pertussis. Outcomes from this research will result in targeting of the dra locus and DMF for developing better vaccines and alternative therapeutics.