Cerebral malaria is a primary cause of malaria-associated deaths, especially in sub-Saharan Africa. There is very poor understanding of the molecular profile of the progression from Plasmodium falciparum regular malaria to cerebral malaria. This hampers the development of prognostic tools for this condition. To this end, in collaboration with Dr. Sanjai Kumar of FDA, we used the Plasmodium berghei ANKA murine model of experimental cerebral malaria and high-density oligonucleotide microarray analyses to identify host molecules that are strongly associated with the clinical symptoms of this condition.
Comparative expression analyses were performed with C57BL/6 mice, which have an experimental cerebral malaria (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 alpha1 proteins by Western blot analysis than mice unaffected by ECM. The higher expression of hemoglobin alpha1 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.
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