Antigenic variation
and transcriptional control in the malaria parasite Plasmodium
falciparum
The research in our laboratory focuses
on the variants antigens (mainly PfEMP1) of Plasmodium falciparum,
and specifically on the mechanisms which orchestrate their expression mode. For this, we manipulate the parasite to introduce molecular switches which permit the controlled expression of a number of nuclear factors potentially involved in the expression of PfEMP1-encoding var genes.
Cytoadhesion of mature parasitized red
blood cells to vascular endothelial cells (sequestration)
and binding of unparasitized red cells to parasitized
ones (rosetting) are considered important virulence factors
in Plasmodium falciparum infections ("Malaria tropica").
Both phenomena depend on the expression of variant parasite
proteins that are exposed on the infected red blood cell
surface. Sequestration and rosetting have been associated
with severe malaria and in particular to cerebral malaria,
responsible for high infant mortality in Africa. The molecular
basis of cytoadhesion and rosetting has been extensively
investigated in recent years and various molecules, from
both the host cells and the parasitized cell membrane
have been identified in these host-parasite interactions.
Various endothelial cell membrane proteins belonging to
the integrin and adhesine families were shown to be receptors
of sequestration. These include CD36, ICAM-1 (inter cellular
adhesion molecule 1), VCAM (vascular cell adhesion molecule),
Endothelial protein C receptor and others. The role
of Chondroitin sulfate A (CSA) was shown as the main receptor for PfEMP1var2csa in the sequestration in placenta
syncythiotrophoblasts.
The PfEMP-1 antigens of P. falciparum (erythrocyte membrane
protein-1), large molecules of 200,000-350,000 daltons,
were identified as parasite ligands responsible for receptor
binding. They are a family of highly polymorphic and antigenically
variant proteins encoded by a multigenic family - the
var genes - composed of 45 to 90 members per haploid genome.
The var genes are distributed in all of the parasite´s
chromosomes with a preferential subtelomeric localization. Expression of var genes is highly coordinated in a way that only one (or a few) var gene is transcribed per infected red blood cell. Then, the active var locus is inherited over the next reinvasions and several epigenetic factors such as histone modifiers and chromatin-binding proteins of the AP2 class are believed to take part in the control of var gene expression memory.
Research goals
Our group is interested in the understanding
of the molecular bases of how P. falciparum blood
stage parasites molecularly control its antigenic variation, especially how the parasite inherits the transcriptional memory over generations.
| Image
1 |
P. falciparum gametocyte isolated
from an asymptomatic infection |
| Image
2 |
PfEMP1 proteins of P. falciparum |
| Image
3 |
Cytoadherence of P. falciparum
infected red blood cells to specific receptors |
Interesting
Malaria links Collaborating
Institute in the Amazon
Research Interest: Immunological recognition
of P. falciparum variant antigens Molecular basis
of var and rif gene transcriptional switching
Research key words Malaria, Plasmodium,
molecular biology, virulent genes, antigenic variation.
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