As M. tuberculosis continues to exert itself as the leading cause of mortality attributed to an infectious
disease, novel treatment strategies are urgently needed. Host-directed therapy (HDT) is an avenue
by which the host immune response can be augmented to drive pathogen clearance and perhaps
lessen the tissue damage associated with chronic infection. When administered alongside standard
chemotherapy, HDT has the potential to reduce treatment duration and ameliorate organ damage
resulting from chronic inflammatory processes. Chapter 1 in this thesis explores innate aspects of the
immune response during infection with M. tuberculosis. I discuss current HDT strategies, including
those in clinical trials. In chapter 2, I examine the melanocortin pathway during mycobacterial
infection. Melanocortin is central to many physiological pathways including food intake, obesity,
pigmentation and steroid neo-genesis. It has also been implicated as an anti-inflammatory agent.
Despite earlier research suggesting an association between melanocortin receptor-4 gene polymorphisms
and susceptibility to M. tuberculosis I was unable to demonstrate any immunological or anti-microbial
benefits using melanocortin receptor agonists, such as melanocyte stimulating hormone. In chapter 3,
I review the role of the inflammasome during M. tuberculosis infection. The inflammasome is an
intracellular multimeric protein comprised of an intracellular sensor (NLR), an adaptor protein called
ASC, and pro-caspase-1. Assembly is induced following stimulation by a physiological and pathological
stimuli. Assembly of the inflammasome leads to the processing of the pro-inflammatory cytokine,
IL-1b. In this chapter I demonstrate that clinical isolates have a differential ability to activate the
inflammasome and induce IL-1b processing. Using immortalised BMDMs carrying null mutations in
individual components of the inflammasome I show that IL-1b can be processed in the absence of
what were previously thought of as critical sensors during M. tuberculosis infection. This led me
to demonstrate that bacterial replication is reduced in conditions where IL-1b release is low. I also
show that that pharmacological blockade of the inflammasome elicits both anti-inflammatory and
anti-microbial activity, and can be used in combination with rifampicin. Interestingly, the anti-microbial
effect afforded by inflammasome inhibition varies with the clinical isolate used. These results show
inflammasome modulation to be highly attractive for the purposes of HDT.