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Title: Host-directed therapy in the treatment of tuberculosis
Author: Subbarao, Sathyavani
ISNI:       0000 0004 8499 390X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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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.
Supervisor: Robertson, Brian.D. ; Cooke, Graham Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral