Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins

Abstract

Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.

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

“…Thus, the extracellular adenosine can act as a "bystander molecule", reducing RBC plasma membrane deformability in cis for iRBCs and in trans for uRBCs [72]. Regardless of the mechanism, reduced deformability may contribute to the microvascular accumulation of Pkand Pf -iRBCs [68,73,74].…”

“…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]. The study found that cytoadherence and sequestration can occur in a subpopulation of Pk iRBCs.…”

“…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].…”

“…This is intriguing because the kidney and lung can be severely damaged in human Pk malaria. In addition, studies of Pk infection in rhesus macaques found that Pk iRBCs were mostly found in the kidney, lung, spleen, gastrointestinal tract, and adrenal gland [74]. It is unclear whether PkDBPα can bind to Duffy antigen in these locations (e.g., renal and pulmonary endothelium).…”