Plasmodium falciparum histidine-rich protein 2 exhibits cell penetration and cytotoxicity with autophagy dysfunction

Plasmodium falciparum is a major cause of severe malaria. This protozoan infects human red blood cells and secretes large quantities of histidine-rich protein 2 (PfHRP2) into the bloodstream, making it a well-known diagnostic marker. Here, however, we identified PfHRP2 as a pathogenic factor produced by P. falciparum. PfHRP2 showed cell penetration and cytotoxicity against various human cells. PfHRP2 also exhibited significant cytotoxicity at concentrations found in P. falciparum-infected patients' blood (90-100 nM). We also showed that PfHRP2 binds to Ca2+ ions, localizes to intracellular lysosomes, increases lysosomal Ca2+ levels, and inhibits the basal level of autophagy by preventing autolysosome formation. Furthermore, the Ca2+-dependent cytotoxicity of PfHRP2 was suppressed by the metal ion chelator ethylenediaminetetraacetic acid. In summary, our findings suggest PfHRP2 as a crucial pathogenic factor produced by P. falciparum and its mode of action. Overall, this study provides preliminary insights into P. falciparum malaria pathogenesis.