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The role of hepatic type cell polarity during Plasmodium liver stage infection

Final Report Summary - POLARITYANDINFECTION (The role of hepatic type cell polarity during Plasmodium liver stage infection)

Malaria remains a major cause of morbidity and mortality in tropical countries, affecting more than 200 million people and causing nearly 1 million deaths every year. Various attempts at eradicating this disease have so far been unsuccessful, and the ever-increasing parasite resistance to older antimalarial drugs provides further cause for concern. This has led to a consensus amongst malaria researchers on the need for detailed understanding of the basic biology of the causative agent of malaria, parasites of the genus Plasmodium, to develop new strategies for malaria prophylaxis, treatment, and hopefully, eradication. The overall goal of this proposal is to work towards elucidation of the host's contribution to Plasmodium parasite growth and development during the liver stages, about which so little is known.

The liver stage constitutes the first obligate step of Plasmodium in the mammalian host, and as the infection is asymptomatic at this stage, an ideal point for antimalarial intervention. After a mosquito deposits sporozoites in the dermis, a significant proportion of these sporozoites enter the blood circulation and rapidly arrest in the liver. A sporozoite then migrates through several cells in the liver, before invading a hepatocyte, which it enters through formation of a parasitophorous vacuole consisting of hepatocyte plasma membrane. Inside this structure, the sporozoite will de-differentiate into an immobile form and commence a period of remarkable growth and division, with potentially thousands of new parasites, termed merozoites at this stage, formed within a single exo-erythrocytic form over a period as short as two days. These merozoites will eventually be released into the bloodstream where they will invade red blood cells, initiating the symptomatic phase of malaria.

While some events of liver stage development can occur in vitro in several cell types, or even outside cells, in vivo, inside the vertebrate host, the only cell type that can support complete growth and development of the EEF into infectious merozoites is the hepatocyte. Thus it appears that the hepatocyte provides a unique niche that allows Plasmodium parasites to grow and replicate. Elucidation of the components of the hepatocyte niche should provide much important insight into the processes that are crucial for Plasmodium EEF growth and development.

Hepatocytes are highly polarised epithelial cells that constitute the liver mesenchyme, acting as blood detoxification centres and playing a critical role for many metabolic events in the body. While epithelial cells are considered to be highly polarised in general, hepatocytes differ substantially from the commonly studied model of simple (or columnar) epithelial polarity, exemplified by Madine-Darby canine kidney (MDCK) cells. Simple epithial polarity is characterised by the presence of basolateral and apical plasma membrane domains, kept separate by the presence of junctional complexes. As its name suggests, the single, continuous apical domain is found at the apex of the cell. Within an organ such as the intestine, the apical domains of many epithelial cells are organised to generate a single, large tube.

In contrast, in hepatocytes the 'apical' region is found laterally, and a single hepatocyte will have more than one such apical membranearea. Neighbouring hepatocytes will polarise such that their apical membrane areas are in direct contact with each other, and this organisation allows the formation of the bile canaliculi, an interconnected network of small tubes designed to move bile through the liver. The type of polarity an epithelial cell adopts has further consequences for arrangement of the cytoskeleton, and the routes taken by proteins as they move to and from the plasma membrane of the cell.