Humoral and cytotoxic effector mechanisms of eliciting protection against Plasmodium sporozoite and liver stage infection

Abstract

The parasites of the Plasmodium genus have arguably caused more deaths than any other pathogen in human history and their ability to evade human immunity has compounded its virulence. The multi-stage life cycle in both vertebrates and mammals, as well as the several forms it takes during its lifecycle, only make investigation of this parasite, and more importantly, how to combat it, extremely difficult. Recent developments in imaging techniques such as intravital imaging, and the ability to observe the parasite transition through these unique morphologies in real time, has enabled researchers to gain a more sound understanding of how the parasite responds to drug designs, immune components and interacts with the vast amount of cell types in the body. In this thesis, these techniques are utilised to investigate how the human immune repertoire interacts with the Plasmodium parasite in live animal models and how the immune system locates, identifies and destroys the parasite.

CD8 T lymphocytes are undoubtedly one of the key cell types in locating and destroying Plasmodium at the liver stage. The ability for these cells to establish and maintain resident populations in the liver, as well as their ability to induce sterilising immunity through clustering and effector responses has been well documented. In addition, their ability to undergo morphological changes and differentiate into effector cells after immunisation is a rather exciting discovery and may play a role in finally developing a long lasting immune response to a vaccine. Recent vaccine strategies utilising entire parasite structures has identified several target sequences on the plasmodium surface which are selectively targeted by Pf(CSP) antibodies and have demonstrated substantial protection in the skin. In addition, these proteins also have the ability to generate effector CD8 T lymphocyte populations in the liver and may explain why protection fails to last in current vaccine designs which only use NANP repeat sequences. The interplay between the activation, migration and residence of CD8 T-lymphocytes, as well as the ability for these cells to execute their effector function at the site of liver infection, and the ability for high affinity antibodies to induce cytotoxicity in the Plasmodium parasites may reveal ideal 'triple whammy' strategies for vaccine design. This thesis investigates these components, and ultimately may help drive the design and generation of a vaccine which incorporates all 3 key immunological phenomena to generate a robust and long lasting vaccine against Plasmodium and reduce the catastrophic disease burden of malaria both in endemic regions and across the globe.