Year: 2013
Type: dissertation
Abstract: Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the only vaccine against tuberculosis (TB). Although in use for nearly a century, it is far from ideal, exhibiting variable protection against pulmonary TB in adulthood and can cause disseminated disease in immunocompromised individuals. Therefore, there is an urgent need to develop more effective and safer TB vaccines than BCG. Understanding molecular factors that influence BCG vaccine properties including safety, immunogenicity, and protective efficacy will help to achieve this goal. This is especially relevant since vaccine candidates designed to boost BCG efficacy have yielded disappointing results in recent clinical trials. Several hypotheses exist for the variable protection of BCG and one of which concerns BCG strain heterogeneity. While it was widely recognized that different BCG strains exhibited varying degrees of virulence and protection in animal models, it has been attributed to quality control issues during the manufacturing process. However, work from our lab suggests that this variability may reflect true biological differences among BCG strains. Notably, we discovered a correlation between the production of the cell wall lipids, phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), and BCG vaccine safety record and between the expression of phoP, the transcriptional regulator in the PhoP-PhoR two-component system, and BCG immunogenicity. Based on these initial observations, the goal of my thesis was to understand the roles of PDIMs/PGLs and PhoP in mediating BCG vaccine clinical properties, including virulence, immunogenicity, and protection. Using mouse models of infection and M. tuberculosis challenge, I found that the loss of PDIMs/PGLs reduces virulence and efficacy of BCG without having an effect on immunogenicity. In examining the role of PhoP, I showed that overexpression of phoP improved protection but also increased virulence of BCG. Taken together, my work has identified two molecular factors that impact BCG vaccine properties and suggests that phoP overexpression may be a novel strategy to improve BCG efficacy. Further, my work suggests that there is an intimate link between BCG virulence and protective efficacy, which provides valuable insight for the selection of BCG strains for current immunization programs and the design of future TB vaccine candidates.
Source: TSpace (University of Toronto)
Author: Linh Vanessa Tran
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2738565062