Exacerbation of pertussis airway inflammation and pathology by pertussis toxin

University Of Maryland Baltimore, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Pertussis (whooping cough) is a respiratory disease of humans caused by acute infection with the gram-negative bacterial pathogen Bordetella pertussis. In the U.S., despite widespread vaccine use, the number of reported cases in 2010 was at a 60-year high, and many other cases go unreported. California experienced its worst pertussis epidemic in 60 years, with 10 infant deaths and over 9000 cases. Individuals suffering from pertussis typically experience debilitating cough episodes that last for weeks, but there is no effective treatment for this disease. B. pertussis infects the respiratory tract and produces a number of toxins that adversely affect the host and modulate host responses. One of these toxins, pertussis toxin (PT), is an important virulence factor uniquely produced by B. pertussis. PT ADP-ribosylates heterotrimeric Gi proteins in mammalian cells, disrupting G protein-coupled receptor (GPCR) signaling pathways and causing a wide range of downstream effects on the cell. PT has several inhibitory effects on the host immune response, including inhibition of innate immune responses that favor bacterial infection. However, our preliminary data demonstrate that PT stimulates multiple inflammatory responses at the peak of B. pertussis infection, including increased expression of a gene encoding an epithelial anion transporter known as pendrin. Pendrin regulates airway surface liquid volume and mucus viscosity, and is implicated in airway pathology in mouse models of asthma and COPD, and therefore represents a potential contributor to pertussis respiratory pathology. We also have preliminary data that PT increases respiratory levels of the inflammatory mediator bradykinin, a peptide implicated in several airway pathologies including cough, and that PT exacerbates respiratory responses to bradykinin. Therefore, we hypothesize that PT is involved in pertussis airway pathology through multiple effects, including upregulation of pendrin on airway epithelium and exacerbation of respiratory responses to bradykinin. Using mouse models of B. pertussis infection combined with complementary in vitro approaches, we will test these hypotheses in two specific aims to determine the roles of these PT-mediated effects in pertussis airway pathology. The broad objective of this project is to understand the role(s) of PT in the respiratory pathology of pertussis disease, with a view to identification of possible targets for novel therapeutics to trea and prevent pertussis.