 |
 |
Lab Projects in Malaria |
|
How does the malaria parasite enter, form a vacuole and acquire extracellular components in the
non-endocytic red cell? Since the 1970s, numerous studies have failed to detect any host proteins
associated with the vacuole of Plasmodium, and this led to some debate on the origin of the
vacuole. Conversely how are parasite proteins exported to the red cell and other secretory
destinations, and how is this regulated by stage specific gene expression? How can whole genome
scanning approaches allow us to translate novel secretory biology into new targets for drug
development?
Host-parasite interactions that underlie vacuolar entry into red cells.
A major breakthrough came in finding that erythrocyte raft proteins (see Figure 5 below) are recruited
into the vacuole by a tubovesicular membrane network (TVN; the TVN is also a major nutrient transport
pathway across the intraerythrocytic space), see Figure 6 below. We are evaluating mutants in each of
these components for their function in vacuolar infection. We are also analyzing raft-signaling
mechanisms that function in malarial invasion. Finally, we are investigating parasite gene products
that interact with erythrocyte raft components in the parasitophorous vacuole as a model to study
host parasite interactions at the molecular level.
|
 |
 |
How do malaria parasites target proteins to specialized secretory destinations? |
|
By tagging genes with GFP and expressing them by transfection, we are mapping routes
and mechanisms of antigen export in live infected red cells. Translocation of proteins across the
parasitophorous vacuolar membrane (surrounding the parasite), the red cell membrane and a secretory
destination called the apicoplast within the parasite. The apicoplast is a newly identified residual
plastid acquired by secondary endosymbiosis that has attracted attention for its evolutionary novelty
and its candidacy as a drug target (see Figure 7 right). |
 |
What are the mechanisms of stage specific gene expression and recombination during blood stage development? |
|
Temporal regulation of plasmodial genes may be important for protein targeting in cells. We are
examining the role of unique promoter elements and chromatin in regulating expression of secretory
determinants such as the histidine-rich proteins and adherence antigens (see Figure 8 right). |
 |
Malaria microarrays to identify drug targets. |
|
Whole genome scanning approaches are being used in combination with informatics to develop novel
lipid linked targets for drug development (Figure 9 right). |
|
