POLARITYANDINFECTION

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

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 Obiettivo del progetto (Objective)

'Plasmodium parasites are the causative agents of malaria, amongst the most prevalent and severe human infectious diseases. Plasmodium sporozoites are injected into the mammalian host during the bite of an anopheline mosquito, and rapidly migrate to the liver where they invade hepatocytes. Once inside a hepatocyte, a single sporozoite initiates a developmental program whereby it gives rise to thousands of merozoites, which are released into the blood stream a few days later, initiating the clinical phase of malaria infection. Sporozoites are capable of entering any cell type tested thus far in vitro, and can even initiate transformation into exo-erythrocytic forms extracellularly, but can only undergo schizogony and generate infectious merozoites in a particular environment, which appears to be provided exclusively by hepatocytes and hepatoma cell lines. This strongly suggests a crucial role of the host cell in providing a distinct niche that supports Plasmodium growth and development. One distinctive feature of hepatocytes when compared to other epithelial cells is their mode of polarization. The general importance of host cell polarity for a liver stage Plasmodium infection has not been investigated. I propose to analyze the role of one unique aspect of hepatocyte biology, the hepatic mode of polarization, in creating the hepatocyte niche that uniquely supports liver stage Plasmodium growth and development. I will address this question by taking a broad approach to characterize the stages of Plasmodium development in WIF-B cells, which display hepatic polarity and to characterize the polarization state of Huh-7 cells, a hepatoma line widely used to assess infection. In a complementary candidate molecule approach, I will characterize the requirement for the host EMK1 kinase, which has a known role in generating hepatic polarity, and the siRNA mediated knockdown of which has a reproducible effect on Plasmodium infection.'

Introduzione (Teaser)

Malaria is holding steadfast to its status as one of the world's most severe infectious diseases. And with increasing resistance to anti-malarial drugs, research is hard pressed to find a solution to the problem.

Descrizione progetto (Article)

The 'The role of hepatic type cell polarity during Plasmodium liver stage infection' (Polarityandinfection) project aimed to provide a better understanding of how the body contributes to the growth and development of Plasmodium parasites after they enter the liver. Insights offered by this study into the basic biology of the Plasmodium parasite, the causative agent of malaria, are expected to enable development of new strategies for protection from malaria, its treatment and perhaps even its eradication.

When bitten by an anopheline mosquito, Plasmodium sporozoites enter the blood stream and rapidly progress to the liver. As infection is without symptoms at the liver stage, this is believed to represent an ideal point for anti-malarial intervention. But sporozoites continue through to the liver, going on to invade hepatocytes.

Hepatocytes act as blood detoxification centres and are of major importance in metabolic events. The Polarityandinfection project noted that the organisation of their highly polarised epithelial cells plays a central role in the routes taken by proteins as they move to and from the plasma membrane of the cell, through which sporozoites originally enter.

Once inside, the sporozoites stabilise and begin to grow and divide. Now termed merozoites, thousands can form in just two days and then be released into the bloodstream where they invade red blood cells. At this point, malarial infection enters the symptomatic or clinical phase.

The study reported that sporozoites can invade any cell type, but they have only been found to generate infectious merozoites in the environment provided by hepatocytes. Uncovering factors contributing to this will provide important knowledge about critical processes involved in Plasmodium growth and development.