Bordetella pertussis is a gram-negative bacterial pathogen that infects the human respiratory tract, leading to a severe paroxysmal coughing disease known as whooping cough that can be fatal in infants. The mechanisms that this pathogen employs to establish an infection and cause disease are still relatively obscure. In addition, although there has been extensive characterization in vitro of the structure and function of several putative 8. pertussis virulence factors, the roles that these factors play in the host-pathogen interaction to promote infection and disease are poorly understood. The overall goal of this project is to determine the role that one of these factors, pertussis toxin (PT), plays in respiratory tract infection by B. pertussis. PT is an exotoxin produced exclusively by this pathogen and can intoxicate a wide range of mammalian cells in culture, but its role in 8. pertussis infection is largely unknown. By comparing a wild type strain (WT) to a mutant strain (APT) with a deletion of the genes encoding PT in a mouse intranasal infection model, we have preliminary data that PT plays an important and early role in colonization of the respiratory tract by 8. pertussis. At least three different immune responses (early neutrophil recruitment to the lungs, early cytokine and chemokine production in the respiratory tract, and serum antibody responses) to infection with WT appear to be suppressed relative to those after infection with APT. Therefore, we hypothesize that an important role of PT is to suppress the antibacterial immune responsesto 8. pertussis, allowing establishment of the infection with subsequent disease pathogenesis. To test this hypothesis we propose four specific aims: (1) to determine the mechanism of inhibition of neutrophil recruitment to the lungs;(2) to determine the relevant targets of PT activity using chemically- and genetically-altered mice;(3) to determine whether PT suppresses lung antibody and T cell responses after 8. pertussis infection;and (4) to determine whether immunosuppression by PT after 8. pertussis infection enhances susceptibility to secondary infections. Elucidation of the specific roles of PT during 8. pertussis infection will increase our understanding of the pathogenic mechanisms of this organism, and may lead to novel therapeutic approaches to combat pertussis infection and disease.
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