Pertussis (whooping cough) is a respiratory disease of humans caused by acute infection with the bacterial pathogen Bordetella pertussis. In the U.S., despite widespread vaccine use, the number of reported cases in 2012 was at a 60-year high, and many other cases go unreported. Several states experienced their worst pertussis epidemic in over 50 years, with multiple infant deaths and thousands of 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. We hypothesized that PT contributes to pertussis infection and disease through multiple effects on the host. We previously found that PT has several inhibitory effects on the host immune response, including inhibition of innate immune responses that favor bacterial infection. However, our preliminary data here demonstrate that PT stimulates multiple airway inflammatory responses at the peak of B. pertussis infection, including increased expression of 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 factors that contribute to airway pathology (such as pendrin) and exacerbation of respiratory responses to inflammatory mediators (such as 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 respirator pathology of pertussis disease, with a view to identification of possible targets for novel therapeutics to treat and prevent pertussis.

Public Health Relevance

Pertussis is a serious and sometimes deadly disease that is re-emerging in epidemics despite widespread vaccination. It is the only vaccine-preventable bacterial infectious disease that is on the rise in this country. The number of reported cases in the U.S. in 2012 was the highest since the early 1950s, 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101055-02
Application #
8660610
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
2013-05-15
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$387,575
Indirect Cost
$109,675
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201