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An investigation into the pre-erythrocytic immune responses that modulate Plasmodium berghei immunopathology and protect against experimental cererbal malaria

Lewis, Matthew

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Cerebral malaria is caused by a complicated series of immune reactions in the host, marked by inflammatory immune responses, margination of leukocytes and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood-brain-barrier. Studies of the immune responses that lead to human cerebral malaria are limited since patients typically present once symptoms have commenced. Along with ethical considerations, this has led to the immunopathogenesis of cerebral malaria being studied in the rodent model. Such studies have generally overlooked the very early stage of infection, during which the malaria parasite invades the liver, despite some evidence that early immune responses and intrahepatic attenuated infections, such as caused by the RTS, S vaccine, play a role in preventing cerebral pathology.

This thesis describes the development of a model that attenuates infection at a very early stage prior to the onset of blood infection by the subtherapeutic administration of isopentaquine, an 8-aminoquinoline. Such chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection and provokes an altered host immune response, altering immunopathogenesis and protecting from cerebral disease. This early response is a pro-inflammatory, cell-mediated one with increased T-cell activation in liver and spleen, elevated numbers of effector T cells, cytokine-secreting T cells and proliferating, multifunctional T cells producing pro-inflammatory cytokines. The response destabilizes the usual series of events that leads to cerebral pathology, by downregulating inflammatory responses and T-cell activation at late infection. Dendritic cell numbers, T-cell activation and infiltration of CD8+ T cells to the brain are decreased in later infection, mediated by the anti-inflammatory cytokine IL-10.

These data indicate that liver-stage-directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome. Strikingly, CD8+ T cells isolated from the spleen as early as day 2 post infection are responsible for protection. Protection can be transferred to naïve animals by adoptive transfer of lymphocytes from the spleen at very early infection, but not when CD8+ T cells are depleted.

The reliance of this phenotype on CD8+ T cells and the transferability of protection are of particular interest, especially since these cells are isolated so early on in infection. Neither attenuated infections or early T cell responses have been studied in relation to cerebral pathology before and this is the first evidence that they can influence the course of the downstream systemic immune response and alter cerebral pathology. This draws parallels with the RTS, S vaccine, which is designed to elicit strong CD8+ T cell responses against the parasite in the liver, and produces similar protection exclusively against severe malaria, including cerebral malaria.

This work has larger implications in dissecting the complex sequence of inter-related events that form the immunological basis of human cerebral (malaria) pathology and uncovers a relationship in both localization and timing of anti-parasitic T-cell responses involved in the immunopathogenesis of cerebral malaria, presenting an insight into the potential role of the preerythrocytic response in tempering downstream cerebral immunopathogenesis. These data support the notion that Th1 cellular responses represent a kill or cure response to Plasmodium that must be tightly controlled in both a spatially and temporally specific manner.

Item Type: Dissertation
Supervisor: Lanzer, Prof. Dr. Michael
Date of thesis defense: 15 July 2013
Date Deposited: 08 Aug 2013 11:44
Date: 15 July 2013
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 000 Generalities, Science
500 Natural sciences and mathematics
570 Life sciences
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