Mechanisms of mycobacterial pathogenesis : Studies in Mycobacterium avium and Mycobacterium marinum

Understanding the basic biology of both a host and the pathogens they are afflicted by is a prerequisite for the development of effective clinical interventions. Mycobacterium tuberculosis, the causative agent of tuberculosis, remains one of the leading causes of disease worldwide. Despite extensive research, the appearance of highly drug-resistant bacterial strains and the prevalence of HIV co-infection in the most vulnerable populations have hindered the eradication of this devastating pathogen. Infections caused by non-tuberculous mycobacteria (NTM) such as Mycobacterium avium are much less common but are increasing globally. NTM infections are exceptionally difficult to diagnose and treat due to highlevels of intrinsic drug resistance, and the relative paucity of knowledge surrounding NTM infections further complicates the development of more effective treatments. Numerous observations have associated the smooth transparent (SmT) morphology of M. avium with human disease, however substantial gaps in knowledge remain regarding the underlying mechanisms of disease establishment and progression. Likewise, while the ESX-1 type VII secretion system is well-established to be a key driver of virulence in M. tuberculosis and close relatives such as Mycobacterium marinum, the exact mechanisms responsible for causing disease remain elusive. Further study of these two virulence determinants is thus an essential step towards understanding mycobacterial pathogenesis, facilitating the development of improved patient treatments. The work undertaken as a part of this thesis investigates how mycobacteria interact with their hosts, focusing on the bacterial and immunological processes that shape infection outcomes.