|Malaria Biology and Genetics|
|HEAD||Dr MÉNARD Robert / firstname.lastname@example.org|
|MEMBERS||Dr BALDACCI Patricia / Dr BLAZQUEZ Samantha / Dr BOISSON Bertrand / Dr BREGA Sara
COMBE Audrey / GIOVANNINI Donatella / Dr GUEIRARD Pascale / Dr ISHINO Tomoko / SPAETH Stefan
Our laboratory focuses on the pre-erythrocytic phase of malaria, i.e., the parasite (Plasmodium) journey from the site of the mosquito bite to the liver and the parasite’s development in the liver. Our major aim is a functional understanding of the important host-parasite interactions that occur during the parasite journey as well as inside the hepatocyte. For this, we use a combination of molecular genetics, cell biology and in vivo imaging approaches.
In vivo imaging of the parasite
In 2006, we showed that a proportion of the sporozoites left at the site of bite by the mosquito undergo a complete development to infectious merozoites inside dermal fibroblasts, indicating that antigens of developing parasites might be presented not only in the liver and the draining lymph node (as we showed in 2005), but also in the skin.
We have also addressed the role of the host cell traversal capacity of the sporozoite. The sporozoite can invade host cells inside a vacuole (termed cell infection), a prerequisite for complete parasite differentiation, or can disrupt host membranes and migrate through and out of cells. The current model is that sporozoites must traverse hepatocytes to acquire competence for cell infection. We have found that cell traversal is important in the dermis, for escaping phagocytosis, and impedes, rather than activates cell infection. We now propose a model where cell traversal permits sporozoite progression from the dermis to the liver parenchyma, where it must be inhibited to allow final infection.
We have also studied how merozoites formed inside hepatocytes reach the bloodstream in liver sinusoids. The motile merozoites were thought to be released individually from bursting hepatocytes. Rather, we observed that intracellular parasites induce the budding of cell extensions that we called merosomes. These merosomes, which detach from the mother cell and later release merozoites, protect the latter from phagocytosis by Kupffer cells by impeding the exposure of “eat-me” signals on the merosome surface.
Dissecting the molecular basis of cell infection by the sporozoite
In 2006, we established a new conditional mutagenesis technique for inactivating any gene specifically in the salivary gland sporozoite, the parasite stage fully infectious to the mammalian host, a technique that also allows for real-time imaging of mutants in rodents. We have also generated parasite clones expressing proteins of interest fused to fluorescent proteins, Using these two approaches, we are currently studying the role of four major surface proteins of the sporozoite.
Identifying new proteins of interest in the pre-erythrocytic stages (PES) of the parasite
We have finalized our SAGE analysis of the sporozoite as well as our in silico screen of genes potentially expressed only in liver stages of the parasite. These two approaches have identified ~100 new genes that are likely to play an important role in the PES of the parasite. On the basis of expression profile or sequence of the encoded proteins, we have selected and mutagenized 20 of these genes. Five of the mutants have a defective phenotype, which are currently being characterized.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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