Cytoadherence Properties of Plasmodium knowlesi-Infected Erythrocytes

Abstract

Plasmodium knowlesi is responsible for zoonotic malaria infections that are potentially fatal. While the severe pathology of falciparum malaria is associated with cytoadherence phenomena by Plasmodium falciparum-infected erythrocytes (IRBC), information regarding cytoadherence properties of P. knowlesi-IRBC remained scarce. Here, we characterized the cytoadherence properties of RBC infected with the laboratory-adapted P. knowlesi A1-H.1 strain. We found that late-stage IRBC formed rosettes in a human serum-dependent manner, and rosettes hampered IRBC phagocytosis. IRBC did not adhere much to unexposed (unstimulated) human endothelial cell lines derived from the brain (hCMEC/D3), lungs (HPMEC), and kidneys (HRGEC). However, after being “primed” with P. knowlesi culture supernatant, the IRBC-endothelial cytoadherence rate increased in HPMEC and HRGEC, but not in hCMEC/D3 cells. Both endothelial cytoadherence and rosetting phenomena were abrogated by treatment of P. knowlesi-IRBC with trypsin. We also found that different receptors were involved in IRBC cytoadherence to different types of endothelial cells. Although some of the host receptors were shared by both P. falciparum- and P. knowlesi-IRBC, the availability of glycoconjugates on the receptors might influence the capacity of P. knowlesi-IRBC to cytoadhere to these receptors.

Experimental Models to Study the Pathogenesis of Malaria-Associated Acute Respiratory Distress Syndrome

“…Moreover, reduced blood volume was documented in patients with vivax -induced MA-ARDS ( Anstey et al., 2007 ). Together, these evidences are in support of recent reports demonstrating that parasite cytoadherence to the endothelium and deep tissue sequestration are not restricted to falciparum but extend to other Plasmodia infecting humans, such as P. vivax ( Carvalho et al., 2010 ; Lopes et al., 2014 ) and P. knowlesi ( Miller et al., 1971 ; Fatih et al., 2012 ; Lee et al., 2021 ).…”

“…Thus, demonstrating that vivax -iRBCs do possess the ability to sequester. This phenomenon was also recently described for P. knowlesi -iRBCs that CD36 was a potential binding receptor on HLECs, with enhanced binding when primed with parasite culture supernatant in vitro ( Lee et al., 2021 ). Although, at present the parasite cytoadherence ligands of vivax -iRBCs and knowlesi -iRBCs are yet to be fully defined, sequestration mediated through ligands such as vivax -derived variant interspersed repeats (VIR) proteins and knowlesi -derived schizont-infected cell agglutination (SICA) proteins have been suggested ( del Portillo et al., 2001 ; Korir and Galinski, 2006 ).…”

Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

“…The occurrence of severe forms of P. vivax infections, such as cerebral and placental malaria, which were previously reported to be exclusively associated with P. falciparum , suggests that P. vivax can, to some extent, present adhesive phenotypes, even if it does not present any protein homologous to Pf EMP1 ( Totino and Lopes, 2017 ). Rosette formation, when uninfected RBCs adhere to iRBCs, appears in P. falciparum , P. vivax ( Lee et al., 2014 ) , and P. knowlesi , even though in the latter with less frequency and in the presence of human serum ( Lee et al., 2021 ). Knob formation and sequestration are distinct characteristics of Pf-iRBCs.…”

“…Knob formation and sequestration are distinct characteristics of Pf-iRBCs. Pk-iRBCs ( Russell and Cooke, 2017 ) do not develop knobs, but still can bind to lung and kidney endothelial cells primed with P. knowlesi culture supernatant via a functional ortholog of Pf EMP1, although not to the cerebral endothelium ( Lee et al., 2021 ). Such novel findings on the capability of other Plasmodium species to undergo cytoadhesion beyond P. falciparum will require further investigations that can be addressed by the use of biophysical approaches and concepts.…”

Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins

“…A few studies have examined cytoadhesion of P. knowlesi T/S-iRBCs using ex vivo ( Fatih et al., 2012 ) and in vitro ( Lee et al., 2022 ) cultivated parasites, leaving questions as to the parasite ligand(s) involved and the number and types of possible host receptor specificities. Critically, in vitro cultivated P. knowlesi iRBCs have been shown to lose expression of the SICAvar gene family, and these were classified in the ‘off state’ with regards to SICAvar expression ( Lapp et al., 2015 ).…”