How Interactions Between Host Immunity And Bacterial Virulence Genes Affect Transmission Of Bordetella Bronchiseptica
Open Access
- Author:
- Rolin, Olivier Yues
- Graduate Program:
- Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 04, 2012
- Committee Members:
- Eric Thomas Harvill, Dissertation Advisor/Co-Advisor
Peter John Hudson, Committee Member
Leslie Joan Parent, Committee Member
Margherita Teresa Anna Cantorna, Committee Member
Mary J Kennett, Committee Member
Andrew Fraser Read, Special Member - Keywords:
- Bordetella
Virulence
Transmission
Immunology
Toll Like Receptor - Abstract:
- Effective strategies to reduce infectious disease burden require a sophisticated understanding of the pathogenesis and life cycle of the targeted microbe. The perpetuation of bacterial pathogens follows a sequence of events that includes 1) entry into a host 2) replication and evasion of host immunity and 3) shedding and transmission to new hosts. Progression of pathogens through transmission cycles requires adaptations for survival and growth within specific host environments, as well as virulence factors that underlie disease processes. Most studies of bacterial pathogenesis give special attention to how virulence factors interact with host immunity to affect within host growth and disease, but overlook events during the initial phases of infection that facilitate entry into new hosts, and those affecting shedding and transmission to new hosts. Investigating how host-pathogen interactions affect entry and exit of pathogens from hosts during transmission cycles can generate a more holistic understanding of disease dynamics and provide new means for interrupting the circulation of pathogens throughout populations. This thesis will examine how host immunity and bacterial virulence factors affect the transmission of Bordetella between hosts. The Bordetella genus comprises numerous species of respiratory pathogens, the most notable of which are the causative agents of whooping cough in humans, Bordetella pertussis (B. pertussis) and Bordetella parapertussis (B. parapertussis), and their ancestral species, Bordetella bronchiseptica (B. bronchiseptica), which circulates widely among wild and domesticated animals. The pathogenesis mechanisms of Bordetella have been studied extensively and vaccines against B. pertussis and B. bronchiseptica effectively protect the majority of individuals from severe disease (1). However, the vaccines are less effective at protecting immunized individuals against less severe manifestations of the disease (2). Therefore, despite far-reaching efforts to control Bordetella-related disease, current interventions have low efficacy in preventing transmission of Bordetella (2, 3, 4), prohibiting achievement of herd immunity and leaving susceptible individuals, particularly infants who have not yet been vaccinated and immunocompromised individuals, at risk for severe disease. This work describes the development a reliable methodology for measure transmission of the B. bronchiseptica from infected mice to naive mice and demonstrates that Toll Like Receptor 4 is a central element of the immune response that affects the resistance of naïve hosts to initial colonization, as well as the control of disease within the host and the intensity of bacterial shedding. We also demonstrate that numerous virulence factors are required for transmission regardless and that certain virulence factors with negligible or subtle contributions to disease pathogenesis have significant and measurable contributions to transmission. Additionally, this thesis seeks to shed light compelling and poorly understood aspects of transmission using Bordetella species as model bacterial pathogens: (1) Are there determinants of shedding independent of bacterial burden? (2) What are the essential defense mechanisms at the mucosal interface? (3) How is disease related to transmission?