Plasmodium falciparum proteins involved in cytoadherence of infected erythrocytes to chemokine CX3CL1

Abstract

Malaria caused by Plasmodium falciparum is associated with cytoadherence of infected red blood cells (iRBC) to endothelial cells. Numerous host molecules have been involved in cytoadherence, including the adhesive chemokine CX3CL1. Most of the identified parasite ligands are from the multigenic and hypervariable Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family which makes them poor targets for the development of a broadly protective vaccine. Using proteomics, we have identified two 25-kDa parasite proteins with adhesive properties for CX3CL1, called CBP for CX3CL1 Binding Proteins. CBPs are coded by single-copy genes with little polymorphic variation and no homology with other P. falciparum gene products. Specific antibodies raised against epitopes from the predicted extracellular domains of each CBP efficiently stain the surface of RBC infected with trophozoites or schizonts, which is a strong indication of CBP expression at the surface of iRBC. These anti-CBP antibodies partially neutralize iRBC adherence to CX3CL1. This adherence is similarly inhibited in the presence of peptides from the CBP extracellular domains, while irrelevant peptides had no such effect. CBP1 and CBP2 are new P. falciparum ligands for the human chemokine CX3CL1. The identification of this non-polymorphic P. falciparum factors provides a new avenue for innovative vaccination approaches.

The Plasmodium falciparum protein VCAP1 controls Maurer’s cleft morphology, knob architecture and PfEMP1 trafficking

“…We identified PF 3D7_1301700 and PF 3D7_0113900, for which there are conflicting reports with respect to the cellular location, ranging from the RBC cytosol in gametocytes (27), to the Maurer’s clefts in asexual stages (28), to the RBC surface (29). These proteins have been previously referred to as gametocyte exported protein 7 (GEXP07) / CX3CL1-binding protein 2 (CBP2) and GEXP10/ CBP1 (27, 29). Based on functional data described below we now refer to PF 3D7_1301700 as the virulence complex assembly protein 1 (VCAP1).…”

“…Immunofluorescence microscopy of samples co-labelled with antibodies recognising GFP and REX1 confirmed that the proteins are directed to the Maurer’s clefts (Fig S2A). A previous study suggested that VCAP1 and GEXP10 are present at the RBC surface (29). While the presence of a small sub-population at the RBC surface or in the RBC cytoplasm cannot be ruled out, our immunofluorescence microscopy shows that the bulk of the protein is located at the Maurer’s clefts (Fig 2; Fig S2A).…”

<p>Immunoinformatics and Vaccine Development: An Overview</p>

“…95,96 The PfEMP1 proteins were identified as the prime ligands responsible for cytoadherence and resetting. 97 They cause the infected RBCs of host tissues to sequester thus helping the parasite to circumvent clearance by the host's spleen. 98 The membrane proteins also shield infected host cells from destruction by the spleen by adhering to the endothelium.…”

“…In this way, only one particular protein at the surface of the infected RBC is expressed at any given time. 97,100 When studying antigenic-variant-protein families, it is pertinent to understand if grouping them into single-family results in any meaningful antigenic activity. Studies have tried to understand the "languages" of the antigenic variant of PfEMP1 proteins.…”

“…Studies have tried to understand the "languages" of the antigenic variant of PfEMP1 proteins. 97,101,102 They sought to know the PfEMP1 proteins binding properties or search to understand the correlation between motifs and infection severity.…”