Clonal Variants of Plasmodium falciparum Exhibit a Narrow Range of Rolling Velocities to Host Receptor CD36 under Dynamic Flow Conditions

Abstract

c Cytoadhesion of Plasmodium falciparum parasitized red blood cells (pRBCs) has been implicated in the virulence of malaria infection. Cytoadhesive interactions are mediated by the protein family of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). The PfEMP1 family is under strong antibody and binding selection, resulting in extensive sequence and size variation of the extracellular domains. Here, we investigated cytoadhesion of pRBCs to CD36, a common receptor of P. falciparum field isolates, under dynamic flow conditions. Isogeneic parasites, predominantly expressing single PfEMP1 variants, were evaluated for binding to recombinant CD36 under dynamic flow conditions using microfluidic devices. We tested if PfEMP1 size (number of extracellular domains) or sequence variation affected the pRBC-CD36 interaction. Our analysis showed that clonal parasite variants varied ϳ5-fold in CD36 rolling velocity despite extensive PfEMP1 sequence polymorphism. In addition, adherent pRBCs exhibited a characteristic hysteresis in rolling velocity at microvascular flow rates, which was accompanied by changes in pRBC shape and may represent important adaptations that favor stable binding.

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

“…However, binding behavior to CD36 is controversial. In agreement with the current study, Herricks and colleagues observed rolling adhesion of isogeneic IEs over a microfluidic slide coated with CD36 40 . Rolling adhesion was also observed over human dermal microvascular ECs, which express numerous CD36 molecules on their surface (86 ± 14 × 10 6 molecules/mm 2 ) 41 .…”

Rolling Adhesion of Schizont Stage Malaria-Infected Red Blood Cells in Shear Flow

“…Cytoadherence on HDMECs is mediated by CD36 and ICAM-1 (22)(23)(24), of which they have been measured to contain 86 5 14 Â 10 6 and 6 5 3 Â 10 6 molecules/mm 2 , respectively (22). However, ICAM-1 is thought to be the primary ligand for rolling, whereas CD36 supports rolling adhesion only within a narrow velocity range and is mainly considered as ligand for firm adhesion (22,24,37).…”

“…Cytoadherence on HDMECs is mediated by CD36 and ICAM-1 (22)(23)(24), of which they have been measured to contain 86 5 14 Â 10 6 and 6 5 3 Â 10 6 molecules/mm 2 , respectively (22). However, ICAM-1 is thought to be the primary ligand for rolling, whereas CD36 supports rolling adhesion only within a narrow velocity range and is mainly considered as ligand for firm adhesion (22,24,37). Wallshear stresses in the range from 0.03 to 0.10 Pa (corresponding to shear rates from 42 to 142 Hz) were chosen to represent the range of physiological hydrodynamic conditions under which rolling adhesion iRBCs occurs in postcapillary venules and sinusoids (68)(69)(70).…”

“…The main host ligand that leads to firm adhesion to microvascular endothelium cells is CD36, whereas rolling is believed to be mediated mainly by ICAM-1 (20)(21)(22)(23)(24).…”

In silico guided reconstruction and analysis of ICAM-1-binding var genes from Plasmodium falciparum

“…All are of DBLα type 0 with varying sub-classifications, a type almost exclusively associated with UPS B and C var genes 4 , concordant with our UPS typing. Similarly, the six genes analysed all contain CIDRα subtypes predicted to bind CD36, a phenotype of UPS B and C type var genes 17 . BC12a, J1a and J1d contain DBLβ5 which is predicted to mediate binding to ICAM-1 18 , 19 .…”