Scientific Publications by FDA Staff

Infect Immun 2008 Oct;76(10):4518-29

Host Biomarkers and Biological Pathways that are Associated with the Expression of Experimental Cerebral Malaria in Mice.

Oakley MS, McCutchan TF, Anantharaman V, Ward JM, Faucette L, Erexson C, Mahajan B, Zheng H, Majam V, Aravind L, Kumar S

Cerebral malaria (CM) is a primary cause of malaria-associated deaths in young African children. Yet there are no diagnostic tools available that could be used to predict which of the children infected with Plasmodium falciparum malaria will progress into CM. We used the P. 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 in the ECM susceptible phenotype C57BL/6 mice and in the ECM resistant phenotypes CD8 knockout and perforin knockout mice on the C57BL/6 background and in BALB/c mice that allowed the identification of over 200 host molecules (a majority previously not identified) with altered expression patterns in the brain that are strongly associated with the manifestation of ECM. Among these host molecules, brain samples from ECM mice had a significantly higher protein expression of the p21, metallothionein and hemoglobin alpha 1 molecules by western blot analysis, suggesting their possible utility as prognostic biomarkers of CM in humans. We suggest that the higher expression of hemoglobin alpha 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.