Recurrent Fever Promotes Plasmodium falciparum Development in Human Erythrocytes

The human malarial parasite Plasmodium falciparum (Pf) is exposed to wide temperature fluctuations during its life cycle, ranging from 25°C in the mosquito vector and 37°C in humans to 41°C during febrile episodes in the patient. The repeated occurrence of fever at regular intervals is a characteristic of human malaria. We have examined the influence of repeated exposure to elevated temperatures encountered during fever on the intra-erythrocytic development of the parasite. Using flow cytometry, we show that repeated exposure to temperatures mimicking febrile episodes promotes parasite development in human erythrocytes. Heat shock-mediated cytoprotection and growth promotion is dependent on the heat shock protein 90 (PfHsp90) multi-chaperone complex. Inhibition of PfHsp90 function using geldanamycin attenuates temperature-dependent progression from the ring to the trophozoite stage. Geldanamycin inhibits parasite development by disrupting the Pf-Hsp90 complex consisting of PfHsp70, PfPP5, and tubulin, among other proteins. While explaining the contribution of febrile episodes to the pathogenesis of malaria, owr results implicate temperature as an important environmental cue used by the parasite to coordinate its development in humans.