Scientific Publications by FDA Staff

Infect Immun 2007 Apr;75(4):2012-25

Molecular Factors and Biochemical Pathways Induced by Febrile Temperature in Plasmodium falciparum Parasites.

Oakley MS, Kumar S, Anantharaman V, Zheng H, Mahajan B, Haynes JD, Moch JK, Fairhurst R, McCutchan TF, Aravind L

Kumar S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA Uniformed Serv Univ Hlth Sci, Emerging Infect Dis Program, Bethesda, MD 20814 USA Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA Walter Reed Army Inst Res, Silver Spring, MD USA USN, Med Res Ctr, Silver Spring, MD USA

Intermittent episodes of febrile illness are the most benign and recognized symptom of infection with malaria parasites, although the effect on parasite survival and virulence remains unclear. In this study, we identified the molecular factors altered in response to febrile temperature by measuring differential expression levels of individual genes using high-density oligonucleotide microarray technology and by performing biological assays in asexual-stage Plasmodium falciparum parasite cultures incubated at 37 degrees C and 41 degrees C (an elevated temperature that is equivalent to malaria induced febrile illness in the host). Elevated temperature had a profound influence on expression of individual genes; 336 of approximately 5300 genes (6.3% of the genome) had altered expression profiles. Of these, 163 genes (49%) were upregulated by 2 fold or greater, and 173 genes (51%) were downregulated by 2 fold or greater. In-depth sensitive sequence-profile analysis revealed that febrile temperature-induced responses caused significant alterations in the major parasite biologic networks and pathways and that these changes are well coordinated and intricately linked. One of the most notable transcriptional changes occur in genes encoding proteins containing the predicted Pexel motifs that are exported into the host cytoplasm or inserted into the host cell membrane and are likely to be associated with erythrocyte remodeling and parasite sequestration functions. Using our sensitive computational analysis, we were also able to assign biochemical or biologic functional predictions for at least 100 distinct genes previously annotated as "hypothetical". We find that cultivation of P. falciparum parasites at 41 degrees C leads to parasite death in a time-dependent manner. Presence of the "crisis forms" and the TUNEL-positive parasites following heat treatment strongly supports the notion that an apoptosis-like-cell-death mechanism might be induced in response to febrile temperatures. These studies enhance the possibility for designing vaccines and drugs based on disruption in molecules and pathways of parasite survival and virulence activated in response to febrile temperatures.