Targeted Disruption of a Ring-infected Erythrocyte Surface Antigen (RESA)-like Export Protein Gene in Plasmodium falciparum Confers Stable Chondroitin 4-Sulfate Cytoadherence Capacity

Abstract

Background: Factors that influence the cytoadherence property of P. falciparum are not completely understood. Results: Targeted disruption of the gene that encodes a RESA-like protein in P. falciparum results in stable and increased chondroitin 4-sulfate-dependent cytoadherence capacity. Conclusion: A RESA-like protein gene regulates PfEMP1 expression and cytoadherence of P. falciparum. Significance: Our findings provide a significant insight into the regulation of P. falciparum cytoadherence.

Genome-Wide Analysis of the Malaria Parasite Plasmodium falciparum Isolates From Togo Reveals Selective Signals in Immune Selection-Related Antigen Genes

“…In Pf isolates from Togo, within genes that are likely under signals of recent positive selection, host immunity-related antigen genes have been the major selective agents. In terms of the top outlier genes (top 1% |iHS| as a strong hits threshold and GO enrichment analysis), 31 of the 306 genes with known functions included six RBC invasion-linked antigen genes (msp1, msp7, mspdbl1, mspdbl2, ra, and sera6) (32, 41) and 22 antigen genes (six rifs, seven vars, and eight stevors) that are associated with roles in evasion to host immunity, rosetting or cytoadhesion (35)(36)(37), among which is var2csa, a pregnancy placental malaria-related gene (34,47) (Table 3). Potential interest for GO analysis for genes under balancing selection by host immune system revealed six genes related to RBC invasion (aarp, flp, msp3, msp7, pl, and sera5) (32), one var (PF3D7_0302300) associated with pathogenesis (GO: 0009405), and phistb rpl1 that is implicated in placental cytoadherence to microvasculature (47).…”

“…Similarly, 134 genes implicated in roles for immune evasion, RBCs aggregation, or cytoadherence to microvasculature (73 rifs, 50 vars, and 12 stevors) were identified ( Supplementary Table 7), of which six rifs, seven vars, and eight stevors ( Table 3) previously as targets of acquired immunity and may serve to prevent severe malaria (42)(43)(44)(45)(46). Furthermore, the var2csa that is implicated in pregnancy placental malaria (34,47) was also observed in the top highest haplotype scores. Overall, iHS values aligned onto those obtained from Tajima's D analysis.…”

Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria

“…These include the DNAJ genes, which encode molecular chaperones in other eukaryotes, but are thought to facilitate interactions with the erythrocyte skeleton and possibly control knob formation in Laverania parasites 49 50 . These also include genes that encode proteins belonging the poly-helical interspersed subtelomeric subclass b (PHISTb) family, which localize to the erythrocyte periphery 51 and in some instances interact with proteins of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family that are encoded by var genes 24 52 . Thus, the rapid expansion and diversification of the FIKK gene family likely occurred in concert with other exported multigene families 48 , which may be responsible, at least in part, for the unique biology of Laverania parasites, including their ability to mediate RBC cytoadhesion, tissue sequestration and/or host immune escape 8 24 .…”

Characterization of a novel secretory spherical body protein in Babesia orientalis and Babesia orientalis-infected erythrocytes

“…In Plasmodium spp., many proteins were reported to be discharged into the cytoplasm or cytoplasmic face of iRBC to internalize and stabilize the host cell environment for parasite survival and replication [ 16 – 18 , 52 – 54 ]. For example, ring-infected erythrocyte surface antigen (RESA) proteins were secreted by dense granules, and then were located to the cytoplasmic face of iRBC through binding the repeat 16 of beta-chain for stabilizing the spectrin tetramer against mechanical and thermal damage [ 16 , 17 , 54 ]. Dense granule antigens (GRAs), secreted by Toxoplasma gondii , were regarded as important targets for the diagnosis and development of vaccines [ 55 , 56 ].…”