Portrait of a pathogen

Mycobacterium tuberculosis is a bacterial agent that causes the disease tuberculosis in human. Tuberculosis is still one of the leading causes of death by an infectious disease and has been so for thousands of years. In 2020, there was a 130 new tuberculosis cases per 100 000 and 1.2 million people have died as a direct consequence of infection by M. tuberculosis.The situation is especially desperate in countries such as South Africa, where there is a high burden and prevalence of drug resistant mycobacterial strains. It is thus important to further study this pathogen and gain a fundamental understanding of it in order to effectively combat the disease. M. tuberculosis is a dangerous and specialised lung pathogen with a small genome specifically evolved to survive within the hostile environment of a macrophage. The hallmark of tuberculosis infection is a phenomenon where the bacilli is surrounded by immune cells to form a granuloma. This harsh environment stimulates a competitive co-evolution between M. tuberculosis and humans where the bacilli becomes more specialised in both its genome and the expression of these genes. In all living cells proteins form the functional basis and thus the proteins are also responsible for all metabolic functions within the cell as well as its structure. Because of the unique evolution of M. tuberculosis the study of the unique features of its genome and proteome are important to elucidate the source of its success as a pathogen. By focussing research efforts on structures and functions of M. tuberculosis that are unique to the pathogenic mycoabacteria might provide insights into the pathogenicity of M. tuberculosis which can be exploited for better chemotherapies. The type VII secretion system of the mycobacteria presents such an unique characteristic of the pathogenic mycobacteria and is thus a prime candidate for intervention and study. This system is unique to the pathogenic mycobacteria and the ESX-5 system is recently evolved in context with the evolutionary timeline. This system is also responsible for the secretion of PE/PPE proteins which represents approximately 10 percent of the genomes coding potential. Since the PE/PPE proteins are secreted and unique to the pathogenic mycobacteria it represents a good candidate for further study and has previously been shown to interfere with the host immune system. The way these proteins operate as a system is however still largely unknown. In this thesis we studied a knock out mutant of ppe38 in depth, specifically because it blocks the secretion of PE-PGRS proteins (a sub-family of PE/PPE proteins). With such a major loss in the secretion of proteins supposedly responsible for virulence, studying ppe38 provides us with an opportunity to investigate the effects of PE-PGRS proteins and how unique mycobacterial proteins are able to influence the host. In conclusion, the adoption of proteomics and genomics as well as efforts to standardise this field is ushering in a new era in biological research. With correct use of the technology new insights can be gained in cellular dynamics which was not previously possible. Using this technology we found that even simple organisms such as bacteria has a high degree of complexity where many unknown functions still reside. With regards to the physiology and evolutionary characteristics of M. tuberculosis and its variants we still have much to learn. In this study we gained additional insights into the important systems of M. tuberculosis and how they interact with the host. This lead to forward strides in understanding the bacilli as well as opened doors for further study into the fundamental processes that allows M. tuberculosis to standout as a major pathogen.