Abstract
BackgroundMicroarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays.ResultsThrough a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice.ConclusionOur microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.
Highlights
Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes
We present an analysis of genes differentially expressed in brains from Cerebral malaria (CM)-R and CM-S mice prior to infection, and at the early and late stages of infection with Plasmodium berghei ANKA (PbA)
Identification of genes regulated in brains by PbA infection The ANOVA of microarray data revealed significant gene expression changes over the course of infection in BALB/c (n = 25) mice, CBA/J mice (n = 16), and in C57BL/6 mice (n = 20)
Summary
Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. Cerebral malaria (CM) is one of the most severe complications and is a major cause of death. Both host and parasite genetic factors play important roles in the outcome of malaria infection. In parallel with human studies, malaria susceptibility genes have been mapped in mouse models, and the role of some genes has been demonstrated [2]. It is clear, that a number of malaria susceptibility genes remain to be identified. These include genes, whose expression is likely deregulated upon malaria infection
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