Abstract
Malaria is a major global health problem. Pregnant women are susceptible to infection regardless of previously acquired immunity. Placental malaria is caused by parasites capable of sequestering in the placenta. This is mediated by VAR2CSA, a parasite antigen that interacts with chondroitin sulfate A (CSA). One vaccine strategy is to block this interaction with VAR2CSA-specific antibodies. It is a priority to define a small VAR2CSA fragment that can be used in an adhesion blocking vaccine. In this, the obvious approach is to define regions of VAR2CSA involved in receptor binding. It has been shown that full-length recombinant VAR2CSA binds specifically to CSA with nanomolar affinity, and that the CSA-binding site lies in the N-terminal part of the protein. In this study we define the minimal binding region by truncating VAR2CSA and analyzing CSA binding using biosensor technology. We show that the core CSA-binding site lies within the DBL2X domain and parts of the flanking interdomain regions. This is in contrast to the idea that single domains do not possess the structural requirements for specific CSA binding. Small-angle x-ray scattering measurements enabled modeling of VAR2CSA and showed that the CSA-binding DBL2X domain is situated in the center of the structure. Mutating classic sulfate-binding sites in VAR2CSA, along with testing dependence of ionic interactions, suggest that the CSA binding is not solely dependent on the sulfated CSA structure. Based on these novel PfEMP1 structure-function studies, we have constructed a small VAR2CSA antigen that has the capacity to induce highly adhesion-blocking antibodies.
Highlights
VAR2CSA expressing Plasmodium falciparum parasites cause placental malaria by interacting with chondroitin sulfate A (CSA) on placental syncytiotrophoblasts
In this study we address a number of key questions related to the molecular mechanism behind placental adhesion in Placental malaria (PM): 1) what are the exact minimal structural requirements for VAR2CSA binding to CSA; 2) where is the minimal binding region positioned in the VAR2CSA structural envelope; 3) what type of chemical interaction exists between VAR2CSA and CSA; and 4) can this information be used to design an optimal vaccine antigen?
In this study we have addressed key questions related to the molecular mechanism behind the VAR2CSACSA interaction in PM
Summary
VAR2CSA expressing Plasmodium falciparum parasites cause placental malaria by interacting with chondroitin sulfate A (CSA) on placental syncytiotrophoblasts. Mutating classic sulfate-binding sites in VAR2CSA, along with testing dependence of ionic interactions, suggest that the CSA binding is not solely dependent on the sulfated CSA structure Based on these novel PfEMP1 structure-function studies, we have constructed a small VAR2CSA antigen that has the capacity to induce highly adhesion-blocking antibodies. This, and small-angle x-ray scattering (SAXS) data proposing that VAR2CSA exhibits an overall compact structure [14], suggested a CSA-binding site dependent on multiple domain and interdomain regions. We show that several short VAR2CSA fragments are capable of inducing the production of adhesion-blocking antibodies and that the anti-adhesive antibodies target the proposed CSA-binding region These data provide the first detailed insight into the biochemical nature of the interaction between a PfEMP1 protein and its ligand and show how structure function studies can aid vaccine development
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