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 innateimmune 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.
Pertussis is a serious and sometimes deadly disease that is re-emerging in epidemics despite widespread vaccination. It is the only vaccine-preventable infectious disease that is on the rise in this country. The number of reported cases in the U.S. in 2010 was the highest since the late 1940s, and many more cases go unreported. There is no effective treatment for individuals suffering from the severe debilitating cough associated with pertussis. In this project we plan to study how the bacterium Bordetella pertussis causes this disease, with particular focus on one of its products that contributes importantly to infection and pathology. Our study may provide information that can be used to design new treatments to provide relief to those suffering from the disease and to prevent spread of the disease to unvaccinated infants, who are at risk of death from pertussis.
|Scanlon, Karen M; Snyder, Yael G; Skerry, Ciaran et al. (2017) Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways. Infect Immun 85:|
|Carbonetti, Nicholas H (2016) Bordetella pertussis: new concepts in pathogenesis and treatment. Curr Opin Infect Dis 29:287-94|