Designing and testing holistic computational frameworks for identification of the most effective vaccine and drug targets against human and bovine tuberculosis : A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy at Lincoln University

Abstract

The World Health Organization has considered tuberculosis (TB) a threat with a significant mortality and morbidity rate worldwide. TB is caused by notorious Mycobacterium tuberculosis, which has evolved with successful survival strategies leading to the emergence of drug-resistant TB strains making drugs (first-line TB drugs) and vaccine (BCG) ineffective. The global emergence of tuberculosis is threatening to make one of humankind’s most lethal infectious diseases incurable, with an estimated 10.0 million new TB cases and 1.4 million deaths in 2019. Further, TB affects animals too; bovine tuberculosis primarily affects cattle and it is caused by the etiological agent Mycobacterium bovis. Twenty to thirty per cent of the global livestock population is potentially affected by bovine TB, leading to annual economic losses of more than USD 3 billion globally (Kuria, 2019). This study conducts an in-depth investigation into pathogen-human interactions to gain deeper insights into the evolution of pathogen and their drug resistance mechanisms and uses this understanding to provide potential solutions for effective vaccine and drug development for human and bovine tuberculosis. Our research begins with gaining an understanding of the pathogenesis of human and bovine TB, the interaction of TB bacteria with its host, the host defence mechanism, bacterial survival strategies in evading the host immune response, and in-depth knowledge of the mechanisms of TB drug resistance. The current drug treatment regimen has not changed in nearly 40 years. Although the first-line drugs play a pivotal role in combating TB, the emergence of resistant TB strains due to different survival mechanisms of TB bacteria such as reduced permeability of cell wall preventing drug entry into the cells, mutations in the drug target protein (major hurdle in TB treatment), inactivation of drug molecules with the help of bacterial enzymes, and a transmembrane drug efflux system to expel the drug out from the bacterial cell has heightened the burden of TB globally. BCG is the only licensed vaccine available and has been around for almost a hundred years. BCG (Bacillus Calmette-Guérin) is prepared from a live-attenuated strain of Mycobacterium bovis and it has shown protection in babies and young children. The inefficiency of BCG in not reducing the prevalence of disease and not protecting adults is so far not understood. Some of the crucial factors might include Mycobacterium bovis is less virulent and not a primary causative agent of TB, diversity in TB strains and over-attenuation of presently used BCG strain. The low efficacy of BCG, the emergence of the drug-resistant Mycobacterium tuberculosis strains, and challenges in developing drugs and vaccines have generated an urgent requirement for a powerful and effective therapeutic approach for TB treatment. This study introduces three holistic strategies/frameworks for developing new and effective therapeutic methods for fighting TB.