| dc.description.abstract | Malaria is one of the most life-threatening infectious diseases in humans. It is mostly prevalent in (sub)tropical areas; Sub-Saharan Africa in particular accounts for more than 90% of the cases and deaths. Malaria is a vector-borne disease, caused by parasites of the genus Plasmodium and transmitted by the female Anopheles mosquito. Only six Plasmodium species are able to infect humans; Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, Plasmodium ovale wallickeri, Plasmodium malariae and Plasmodium knowlesi, with P. falciparum being the leading cause of malaria in young African children.
The life cycle of the malaria parasite starts when a female Anopheles mosquito injects infective sporozoites from its salivary gland into the human skin. The sporozoites migrate to the liver, where they infect hepatocytes and grow exponentially. Following their release into the bloodstream, the parasites start infecting red blood cells, which results in the establishment of the first clinical symptoms and can even lead to death of the host. Another mosquito bite transfers free parasites present in the bloodstream back to the mosquito, allowing them to be transmitted to a new human host.
Up until now, the many attempts to reduce the amount of malaria cases have largely been unsuccessful. Bed nets and insecticides are not effective enough, and even though antimalarials are a common way to treat the disease, drug resistance of the parasite is a rising problem. Additionally, the long-term co-evolution between Plasmodium and the human population has pressured the parasite to become highly adaptable to its host, making malaria very hard to eradicate. However, a crucial step towards elimination was made recently, when the first malaria vaccine was officially approved by the World Health Organization. Although the RTS,S vaccine is expected to have a significant effect on improving child survival, research into the parasite’s infection cycle and establishing new therapeutic targets remains important to be able to fully eradicate malaria from the human population.
Because the liver phase of the parasite’s infection cycle is clinically silent, inhibition of successful liver stage development will prevent onset of disease. This makes the liver stage a very interesting target for vaccination. To identify potential therapeutic targets, it is important to fully understand the complex interactions that take place between the malaria parasite and liver cell.
First, successful entry of the malaria parasite into liver cells is mediated by the binding of the circumsporozoite surface protein, the major surface protein of the parasite, to heparan sulfate proteoglycans on the host cell surface. One of the major challenges that the malaria parasite faces within a liver cell is the process of autophagy, which specifically targets the pathogen for elimination. While indeed a lot of the parasites are killed, the majority is able to escape this destruction mechanism. Moreover, it appears that the malaria parasite uses the autophagy pathway to obtain nutrients required for growth and development. Research has also shown that the Plasmodium parasite is able to form close interactions with liver cell organelles, such as the endoplasmic reticulum, golgi network and host mitochondria. In fact, it seems that these connections with the host are necessary for the malaria parasite to survive, probably because they allow the pathogen to secure building blocks and nutrients. The liver stage of the parasite’s infection cycle thus contains lots of possibilities for therapeutic intervention. This thesis therefore elaborates on the various host factors that are utilized by the malaria parasite to complete liver stage development and gives insight into how these interactions enable therapeutic intervention. | |
