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Differences in antigen presentation between sporozoite and parasitised-erythrocyte infections uncovers divergent mechanisms in the development of experimental cerebral malaria

Fernandes, Priyanka Noel

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Abstract

Cerebral malaria (CM) is one of the most severe manifestations of Plasmodium falciparum, characterised by seizures, coma and death within a short time period. The aetiology of the disease remains poorly understood and is limited by ethical constraints in dealing with human patients. A large body of research dedicated to CM has therefore focussed on delineating the mechanisms involved using the rodent model of malaria. Infection of mice with sporozoites or infected red blood cells (iRBCs) of PbANKA parasites recapitulates several features of CM including haemorrhaging, oedema and blood-brain barrier breakdown and is termed experimental CM (ECM).

The development of ECM relies on a complex series of interactions between the parasite and host. Although regarded as an immune-mediated pathology, sequestration of iRBCs is considered a central event for ECM to ensue, thus supporting the notion that ECM is purely the outcome of host-parasite interactions at the pathological blood stage. However, previous studies have shown that both surface antigens of iRBCs and the host’s immune response differ between naturally transmitted (sporozoites) and blood-passaged parasites. This thesis is therefore aimed at describing the role of a novel Plasmodium antigen in the development of ECM and outlining differences in ECM progression between naturally transmitted and blood-passaged parasites.

The antigen, PbmaLS_05 is expressed in both liver-stage- and blood-stage schizonts and localises to the apicoplast of individual merozoites. Deletion of the endogenous PbmaLS_05 had no effect on parasite viability, but abrogated the development of ECM in mice, after both sporozoite and iRBC infections. PbmaLS_05 (-) parasites displayed retarded growth rates in the blood and enhanced clearance by the spleen, both of which were more pronounced on the days when PbANKA wild type infected mice showed signs of ECM. The absence of ECM in PbmaLS_05 (-) infected mice was accompanied by reduced infiltration of activated CD8+ T cells within the brain and reduced cross-presentation of a known parasite antigen (GAP50) by the brain endothelium, after iRBC but not sporozoite infection. Further investigations into sporozoite infections revealed an important role for PbmaLS_05 in the priming of CD8+ T cells responsible for causing ECM. These data thus highlight the existence of multiple mechanisms leading up to the development of ECM relevant to sporozoite or iRBC infections, with potential implications for vaccines or therapeutics designed to alleviate CM.

Item Type: Dissertation
Supervisor: Mueller, Dr. Ann-Kristin
Date of thesis defense: 11 October 2016
Date Deposited: 25 Oct 2016 07:26
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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