Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice.
BACKGROUND
Microarray 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.


RESULTS
Through 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 beta-amyloid proteins in brains of CM-S mice, but not of CM-R mice.


CONCLUSIONS
Our 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.
Delahaye
Nicolas F
NF
Laboratoire de Pharmacogénétique des maladies parasitaires-EA864, Université de la Méditerranée, IFR48, Marseille, France. nicolasdelahaye@yahoo.fr
Coltel
Nicolas
N
Puthier
Denis
D
Barbier
Mathieu
M
Benech
Philippe
P
Joly
Florence
F
Iraqi
Fuad A
FA
Grau
Georges E
GE
Nguyen
Catherine
C
Rihet
Pascal
P
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000469:parasitology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D017125:Genes, Protozoan; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008954:Models, Biological; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010962:Plasmodium berghei / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic
D015800:Protozoan Proteins