Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Administration of anti-malarial drugs, currently the only treatment for the syndrome, fails to prevent mortality or the development of long-term neurological deficits in a significant proportion of CM cases. Consequently, there is an urgent need to understand the pathophysiological processes underlying CM, in order to facilitate the development of adjunct therapies for the disease. However, the experimental murine model of CM (ECM) utilised to understand disease pathogenesis has proven controversial; in particular, because of perceived differences in causal roles for intracerebral pRBCs and CD8+ T-cells in ECM and human (H)CM, and a failure to translate adjunct treatment strategies developed in the murine model to the clinic. Work carried out for this thesis demonstrated that the accumulation of parasitised red blood cells (pRBCs) within the cerebrovasculature is a specific feature of ECM. Importantly, pRBCs appeared to promote haemostasis and impair vascular and neuronal function in the brains of mice, as has been shown to occur in the brains of humans, during malaria-induced encephalopathy. Furthermore, the findings of this thesis indicate that small numbers of CD8+ T-cells similarly accumulate within the perivascular spaces, leptomeningeal vessels and choroid plexus during ECM and HCM. Perivascular CD8+ T-cells appear to be similarly associated with vasogenic oedema in the brains of humans and mice during malaria-induced encephalopathy, suggesting that they may contribute equivalently to ECM and HCM. Thus, this thesis provides significant data reconciling the pathologies of ECM and HCM. Whole brain transcriptomic analyses undertaken in this newly validated model, contrasting the expression profiles of mice in agonal ECM, and in those after anti-malarial drug treatment identified a number of targets for adjunct therapy, including IL33. Results presented in this thesis show that IL33 in conjunction with anti-malarial drugs reduced ECM-associated mortality and neuropathology in Pb ANKA-infected mice over anti-malarial drugs alone, ostensibly by suppressing IL1β production in intracerebral mononuclear phagocytes. Thus, the findings in this thesis indicate that IL1 family members may provide targets for adjunct therapies for treatment of HCM.
Defining the pathogenesis of cerebral malaria and developing adjunct therapies for its treatment using murine models
Strangward, P. (Author). 1 Jan 1824
Student thesis: Phd