Abstract
Malaria is one of the 'Big Three' infectious diseases, together with HIV and tuberculosis. According to the World Health Organisation, malaria is endemic in 104 countries thereby endangering the health and lives of 3.4 billion people. Each year around 200 million cases of the disease are documented, including more than half a million deaths. More than 70% of the deceased are children under the age of five. The etiological agents of malaria are parasites from the Plasmodium genus, of which P. falciparum is the most virulent. Malaria parasites are transmitted by mosquitoes, which inject the parasites into the human body during a blood meal. This initiates the infection, which is characterized by two stages. The first stage (known as liver stage malaria) is caused by a form of the parasite called the sporozoite and is typically asymptomatic. The sporozoite infects the liver and develops into the next form of the parasite called the merozoite. This marks the start of the second stage of the malaria known as the blood stage. This phase, during which merozoites infect red blood cells, causes the infamous malaria pathology.
Sporozoites are ideal targets for anti-malarial therapies as their elimination from the human host would prevent the onset of disease. Therefore, the sporozoite surface proteins are interesting candidates for the development of novel anti-malarial drugs and vaccine strategies. The presented research project aims at unraveling the mechanistic principles behind several processes that are crucial in the establishment of liver stage malaria. The first is the invasion of hepatocytes by the parasite. While it is known that the parasite's main surface antigen, the circumsporozoite protein (CSP), plays a pivotal part in successful hepatocyte invasion, the structural and functional aspects of this event remain unchartered territory. A thorough structural and biophysical study of the molecular aspects of CSP-mediated hepatocyte invasion will provide relevant insights into the biology of the malaria parasite. Once the parasite has invaded a hepatocyte, it forms a vacuole from within which it exports CSP to the host cell cytoplasm. There, CSP competes with NFkB for binding with the importin proteins in order to dampen NFkB-driven inflammatory responses. This increases the odds of parasite survival inside the infected hepatocyte and, hence, ensures continuation of the life cycle. Although it is known that CSP and importin proteins interact, the structural and biophysical aspects of this encounter have not yet been investigated. Obtaining a detailed picture of this interaction will allow a better understanding of immune evasion strategies adopted by the malaria parasite during the liver stage of the infection. Finally, the fundamental mechanism of CSP export from the parasite to the host hepatocyte cytoplasm will also be investigated. As investigating sporozoite antigens has produced significant scientific breakthroughs in the battle against malaria, it is anticipated that tackling the above-mentioned issues will not only yield insights into the parasite's immunobiology, but also generate a molecular basis to contribute to the design of novel anti-malarial therapies.
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