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Infection and Immunity, April 2007, p. 2012-2025, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01236-06

Molecular Factors and Biochemical Pathways Induced by Febrile Temperature in Intraerythrocytic Plasmodium falciparum Parasites ^,

Miranda S. M. Oakley,^1,2 Sanjai Kumar,^3* Vivek Anantharaman,⁴ Hong Zheng,³ Babita Mahajan,³ J. David Haynes,⁵ J. Kathleen Moch,⁵ Rick Fairhurst,¹ Thomas F. McCutchan,¹ and L. Aravind⁴

Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland,¹ Emerging Infectious Diseases Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland,² Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland,³ National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland,⁴ Walter Reed Army Institute of Research and Naval Medical Research Center, Silver Spring, Maryland⁵

Received 3 August 2006/ Returned for modification 22 September 2006/ Accepted 29 December 2006

Intermittent episodes of febrile illness are the most benign and recognized symptom of infection with malaria parasites, although the effects on parasite survival and virulence remain 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°C and 41°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 5,300 genes (6.3% of the genome) had altered expression profiles. Of these, 163 genes (49%) were upregulated by twofold or greater, and 173 genes (51%) were downregulated by twofold 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 occurs 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°C leads to parasite death in a time-dependent manner. The presence of the "crisis forms" and the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive parasites following heat treatment strongly support the notion that an apoptosis-like cell death mechanism might be induced in response to febrile temperatures. These studies enhance the possibility of designing vaccines and drugs on the basis of disruption in molecules and pathways of parasite survival and virulence activated in response to febrile temperatures.

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* Corresponding author. Mailing address: Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852. Phone: (301) 827-7533. Fax: (301) 827-4622. E-mail: Sanjai.kumar{at}fda.hhs.gov.

Published ahead of print on 5 February 2007.

Editor: W. A. Petri, Jr.

Supplemental material for this article may be found at http://iai.asm.org/.

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Infection and Immunity, April 2007, p. 2012-2025, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01236-06

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