Medical Biology - Theses

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Author: Yang, Annie Shu-Ping × Type: PhD thesis × Subject: Malaria × Subject: Plasmodium falciparum ×

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    Molecular mechanism of cell traversal by Plasmodium falciparum
    Yang, Annie Shu-Ping ( 2016)
    Malaria is an infectious mosquito-borne disease caused by apicomplexan parasites of the genus Plasmodium. Each year, malaria affects over 200 million people, causing considerable morbidity and mortality. A central feature of the virulence of malaria parasites is the ability of the liver-infective form of the parasite, known as sporozoites, to migrate from the mosquito bite site in the skin through host tissues to the target organ, the liver. The ability of sporozoites to traverse through different host cell types is crucial for the establishment and development of parasites within the mammalian host. Over the past decade, our understanding of traversal has become clearer through important studies using rodent models of malaria, such as P. berghei and P. yoelii. However, it remains unclear how these findings apply to malaria parasite species that infect humans, such as P. falciparum and P. vivax. Furthermore, proteins involved in the process, as well as a step-wise molecular model of it, remain unknown. In order to address these questions, the work presented in this thesis utilises molecular genetics and cellular biology to investigate the role of proteins in the traversal mechanism. Overall, this study has identified a novel role for two well-known proteins, Apical Membrane Antigen 1 (AMA1) and Merozoite Apical Erythrocyte Binding Ligand (MAEBL), in the traversal process. Furthermore, this study has validated the role Sporozoite Protein Essential for Cell Traversal (SPECT) and Perforin-Like Protein 1 (PLP1) in P. falciparum sporozoites, which are two proteins that previously have been identified as playing a crucial role in traversal using rodent models of malaria. Using mice engrafted with human hepatocytes, this study also demonstrated the importance of traversal for P. falciparum sporozoites to establish infection of human hepatocytes in vivo. Together, these findings provide the first molecular understanding of cell traversal by P. falciparum and give valuable insights into the complexity of traversal and allowed the formation of a basic molecular model for this process.