Mechanisms underlying subversion of host immunity by Bordetella pertussis

Bordetella pertussis is a Gram-negative human-adapted pathogen of the respiratory tract and the causative agent of the whooping cough (pertussis) illness. The bacterium produces a number of virulence factors, of which adenylate cyclase toxin (ACT) and pertussis toxin (PT) play important roles in manipulation of host immune response and establishment of the early catarrhal stage of infection. Although the toxins exert their cytotoxic activity by elevation of intracellular cAMP levels, both are distinct from each other in terms of their structures, mechanisms of secretion and cell intoxication, as well as in their ability to modulate the adaptive immune response of the host. The aim of this thesis was to determine the structure- function relationship underlying the mechanism of the Type I secretion system (T1SS)- mediated secretion of ACT and to decipher the immunomodulatory properties of ACT and PT in the course of B. pertussis infection. Integrative structural biology approaches revealed that the RTX domain of ACT consists of a contiguous assembly of five Ca2+ -loaded β-roll blocks, whose co-secretional folding constitute an intramolecular Brownian ratchet that prevents backsliding of the translocating polypeptide in the T1SS conduit, thus accelerating the secretion of ACT from bacterial cells by a..