Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of post-exposure or therapeutic tuberculosis vaccines

Abstract

The growing number of tuberculosis (TB) casualties urges development of not only more effective drugs and preventive vaccines but also development of post-exposure/therapeutic TB vaccines. Post-exposure/therapeutic TB vaccines are needed since 2 billion people worldwide harbor a latent Mycobacterium tuberculosis infection. This vast reservoir forms a major source of new TB cases: one out of every ten M. tuberculosis infected individuals will develop active TB disease at one point in life, while the remainder contains the bacilli without any clinical symptoms. The current vaccine, M. bovis BCG (BCG), is ineffective in already latently infected individuals. In a series of M. tuberculosis antigen discovery studies, aiming at identifying new M. tuberculosis biomarker- and vaccine antigens, we found that genes from the M. tuberculosis DosR regulon encode antigens that can induce specific T-cell immunity in M. tuberculosis infected individuals. We argue that these genes which are expressed by dormant and persisting bacilli may represent attractive targets for post-exposure/therapeutic vaccination against TB. This thesis focuses on the immunologic evaluation of these M. tuberculosis DosR encoded genes in humans and mice regarding immunogenicity, (latent) M. tuberculosis infection, induction of immune responses following BCG vaccination and exposure to environmental, non-tuberculous mycobacteria.