SICA-mediated cytoadhesion of Plasmodium knowlesi-infected red blood cells to human umbilical vein endothelial cells

Abstract

Zoonotic malaria due to Plasmodium knowlesi infection in Southeast Asia is sometimes life-threatening. Post-mortem examination of human knowlesi malaria cases showed sequestration of P. knowlesi-infected red blood cells (iRBCs) in blood vessels, which has been proposed to be linked to disease severity. This sequestration is likely mediated by the cytoadhesion of parasite-iRBCs to vascular endothelial cells; however, the responsible parasite ligands remain undetermined. This study selected P. knowlesi lines with increased iRBC cytoadhesion activity by repeated panning against human umbilical vein endothelial cells (HUVECs). Transcriptome analysis revealed that the transcript level of one gene, encoding a Schizont Infected Cell Agglutination (SICA) protein, herein termed SICA-HUVEC, was more than 100-fold increased after the panning. Transcripts of other P. knowlesi proteins were also significantly increased, such as PIR proteins exported to the iRBC cytosol, suggesting their potential role in increasing cytoadhesion activity. Transgenic P. knowlesi parasites expressing Myc-fused SICA-HUVEC increased cytoadhesion activity following infection of monkey as well as human RBCs, confirming that SICA-HUVEC conveys activity to bind to HUVECs.

Plasmodium knowlesi (Pk) Malaria: A Review & Proposal of Therapeutically Rational Exchange (T-REX) of Pk-Resistant Red Blood Cells

“…Although all blood-stage forms of Pk circulate, recent data suggest that a subset of Pk-iRBCs demonstrate endothelial cytoadherence (sequestration), which is a key mechanism for the microvascular accumulation of Pf -iRBCs [74][75][76][77][78]. A recent study of Pk malaria in rhesus macaques, a non-natural host, was conducted by the Emory National Primate Research Center [74].…”

“…Pk sequestration is likely dependent on Schizont-Infected Cell Agglutination (SICA) antigens. These protein antigens, encoded by the SICAvar gene family, are only expressed on iRBCs when a functional spleen is present [74,77].…”

Plasmodium knowlesiinfection is associated with elevated circulating biomarkers of brain injury and endothelial activation

“…A high proportion of severe Pk infections has been reported in Southeast Asia (5,19), as well as fatal cases (18)(19)(20). A recent study also showed that, similarly to P. falciparum, Pk-infected erythrocytes are able bind to endothelial cells (21). Postmortem findings in one fatal case of severe Pk malaria revealed brain pathology features similar to those seen in fatal falciparum cerebral malaria, including Pk-infected erythrocytes sequestration in the microvasculature (18), suggesting that Pk malaria may also affect the brain.…”