Previous Article | Next Article 
Infection and Immunity, October 2008, p. 4518-4529, Vol. 76, No. 10
0019-9567/08/$08.00+0 doi:10.1128/IAI.00525-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Host Biomarkers and Biological Pathways That Are Associated with the Expression of Experimental Cerebral Malaria in Mice
,
Miranda S. Oakley,1,2
Thomas F. McCutchan,1
Vivek Anantharaman,3
Jerrold M. Ward,4
Laurence Faucette,4
Cindy Erexson,4
Babita Mahajan,5
Hong Zheng,5
Victoria Majam,5
L. Aravind,3 and
Sanjai Kumar5*
Laboratory of Malaria and Vector Research,1 Infectious Disease Pathogenesis Section, Comparative Medicine Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health,4 Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville,5 Emerging Infectious Diseases Program, Uniformed Services University of the Health Sciences,2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland3
Received 29 April 2008/ Returned for modification 5 June 2008/ Accepted 7 July 2008
Cerebral malaria (CM) is a primary cause of malaria-associated deaths among young African children. Yet no diagnostic tools are available that could be used to predict which of the children infected with Plasmodium falciparum malaria will progress to CM. We used the Plasmodium berghei ANKA murine model of experimental cerebral malaria (ECM) and high-density oligonucleotide microarray analyses to identify host molecules that are strongly associated with the clinical symptoms of ECM. Comparative expression analyses were performed with C57BL/6 mice, which have an ECM-susceptible phenotype, and with mice that have ECM-resistant phenotypes: CD8 knockout and perforin knockout mice on the C57BL/6 background and BALB/c mice. These analyses allowed the identification of more than 200 host molecules (a majority of which had not been identified previously) with altered expression patterns in the brain that are strongly associated with the manifestation of ECM. Among these host molecules, brain samples from mice with ECM expressed significantly higher levels of p21, metallothionein, and hemoglobin 
1 proteins by Western blot analysis than mice unaffected by ECM, suggesting the possible utility of these molecules as prognostic biomarkers of CM in humans. We suggest that the higher expression of hemoglobin 1 in the brain may be associated with ECM and could be a source of excess heme, a molecule that is considered to trigger the pathogenesis of CM. Our studies greatly enhance the repertoire of host molecules for use as diagnostics and novel therapeutics in CM.
* Corresponding author. Mailing address: Malaria Research Program, 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 21 July 2008.
Supplemental material for this article may be found at http://iai.asm.org/.
Infection and Immunity, October 2008, p. 4518-4529, Vol. 76, No. 10
0019-9567/08/$08.00+0 doi:10.1128/IAI.00525-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»