Tuberculous Meningitis (TBM) is the most severe form of tuberculosis, affecting >100,000 people/year (Wilkinson et al., 2017, Marais et al., 2011). TBM arises when Mycobacterium tuberculosis crosses the blood-brain barrier, causing severe inflammation and tissue damage (Davis et al., 2019b). Inflammation also initiates metabolic derangement, mediating neuronal injury despite treatment (Davis et al., 2019b, Rohlwink et al., 2019, Rohlwink et al., 2017). In HIV-1 coinfection, TBM mortality is reported to be as high as 50% (Marais et al., 2011). Half of TBM survivors are affected by neurological disability (Thwaites et al., 2003). Thus, improved therapeutic strategies are needed, including targeted and nuanced modification of the injurious host inflammatory response. To develop these, we must understand the immune induced tissue damaging responses and metabolic disturbances contributing to brain damage which drive acute and long-term neurological complications.

The goals of this PhD thesis were to investigate the safety of a novel drug regimen in HIV-associated TBM and through a series of nested sub-studies, understand pathogenic mechanisms of acute and long term neurological sequalae in TBM. Specifically, this thesis presents:

i) A study protocol and results from a phase 2A randomised controlled trial of high dose rifampicin and adjunctive linezolid with and without aspirin in HIV-associated TBM
ii) Results from a case-control study of cognitive and functional outcomes in HIV-associated TBM
iiI) Results from a study investigating in vivo markers of brain injury in HIV-associated TBM via magnetic resonance spectroscopy
iv) Results from a study investigating ex vivo markers of poor outcome via Luminex multiplex analysis of blood and cerebrospinal fluid.

Given the timing of this PhD, this thesis also contains results of an observational case-control study to understand neurological complications of COVID-19 via systematic analysis of cerebrospinal fluid of patients presenting with neurological symptoms during the first wave of the COVID-19 pandemic in South Africa. These results are included within the appendix of the thesis.