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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063080-05
Application #
7737884
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Khambaty, Farukh M
Project Start
2005-12-01
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$400,116
Indirect Cost
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
Carbonetti, Nicholas H (2016) Bordetella pertussis: new concepts in pathogenesis and treatment. Curr Opin Infect Dis 29:287-94
Connelly, Carey E; Sun, Yezhou; Carbonetti, Nicholas H (2012) Pertussis toxin exacerbates and prolongs airway inflammatory responses during Bordetella pertussis infection. Infect Immun 80:4317-32
Worthington, Zoe E V; Van Rooijen, Nico; Carbonetti, Nicholas H (2011) Enhancement of Bordetella parapertussis infection by Bordetella pertussis in mixed infection of the respiratory tract. FEMS Immunol Med Microbiol 63:119-28
Carbonetti, Nicholas H (2010) Pertussis toxin and adenylate cyclase toxin: key virulence factors of Bordetella pertussis and cell biology tools. Future Microbiol 5:455-69
Andreasen, Charlotte; Powell, Daniel A; Carbonetti, Nicholas H (2009) Pertussis toxin stimulates IL-17 production in response to Bordetella pertussis infection in mice. PLoS One 4:e7079
Andreasen, Charlotte; Carbonetti, Nicholas H (2009) Role of neutrophils in response to Bordetella pertussis infection in mice. Infect Immun 77:1182-8
Li, Ge; Bukrinsky, Michael; Zhao, Richard Y (2009) HIV-1 viral protein R (Vpr) and its interactions with host cell. Curr HIV Res 7:178-83
Andreasen, Charlotte; Carbonetti, Nicholas H (2008) Pertussis toxin inhibits early chemokine production to delay neutrophil recruitment in response to Bordetella pertussis respiratory tract infection in mice. Infect Immun 76:5139-48
Carbonetti, Nicholas H; Artamonova, Galina V; Van Rooijen, Nico et al. (2007) Pertussis toxin targets airway macrophages to promote Bordetella pertussis infection of the respiratory tract. Infect Immun 75:1713-20
Carbonetti, Nicholas H (2007) Immunomodulation in the pathogenesis of Bordetella pertussis infection and disease. Curr Opin Pharmacol 7:272-8

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