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J. Biol. Chem., Vol. 279, Issue 45, 46692-46699, November 5, 2004

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Recurrent Fever Promotes Plasmodium falciparum Development in Human Erythrocytes^*

Soundara Raghavan Pavithra, Gowrishankar Banumathy, Omana Joy, Varsha Singh, and Utpal Tatu

From the Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India

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 intraerythrocytic 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 PfHsp90 complex consisting of PfHsp70, PfPP5, and tubulin, among other proteins. While explaining the contribution of febrile episodes to the pathogenesis of malaria, our results implicate temperature as an important environmental cue used by the parasite to coordinate its development in humans.

Received for publication, August 10, 2004 , and in revised form, August 27, 2004.

^* This study was funded by the Indo-French Centre for the Promotion of Advanced Research and the Department of Biotechnology, New Delhi, India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 91-80-22932823; Fax: 91-80-23600814; E-mail: tatu{at}biochem.iisc.ernet.in.

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