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Plasmodium falciparum is the most virulent human malaria parasite due to its ability to cytoadhere in the microvasculature. Non-human primate studies demonstrated a relationship between knob expression, cytoadherence and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8 and 3D7B) and ex vivo-derived cell banks were characterised. Knob and KAHRP expression, CD36 adhesion and antibody recognition of parasitised erythrocytes (PE) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterisation. All parasites were infective in vivo However, infectivity of NF54 was dramatically reduced. In vitro characterisation revealed that unlike other cell bank parasites, NF54 PE lacked knobs and did not cytoadhere. Recognition of NF54 PE by immune sera was observed, suggesting PfEMP1 expression. Subsequent recovery of knob-expression and CD36-mediated adhesion was observed in PE derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in their infectivity and ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restores knob-expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence.