title: Recurrent fever promotes Plasmodium falciparum development in human erythrocytes.
abstract: The human malarial parasite Plasmodium falciparum (Pf) is exposed to wide temperature fluctuations during its life cycle, ranging from 25 degrees C in the mosquito vector and 37 degrees C in humans to 41 degrees 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.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Soundara Raghavan
authors.initials: SR
authors.lastname: Pavithra
authors.forename: Gowrishankar
authors.initials: G
authors.lastname: Banumathy
authors.forename: Omana
authors.initials: O
authors.lastname: Joy
authors.forename: Varsha
authors.initials: V
authors.lastname: Singh
authors.forename: Utpal
authors.initials: U
authors.lastname: Tatu
mesh_terms: D000818:Animals; D016227:Benzoquinones; D001831:Body Temperature; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D004912:Erythrocytes / Q000469:parasitology*; D005334:Fever; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic; D016778:Malaria, Falciparum / Q000469:parasitology* / Q000473:pathology*; D018832:Molecular Chaperones / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors
chemical_list: D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011809:Quinones; C001277:geldanamycin