Gene‐Expression Profiling Discriminates between Cerebral Malaria (CM)–Susceptible Mice and CM‐Resistant Mice

Abstract

The development of cerebral malaria (CM) in mice with Plasmodium berghei ANKA infection is under genetic control. Brain gene-expression patterns were investigated in well-defined genetically CM-resistant (CM-R; BALB/c and DBA/2) and CM-susceptible (CM-S; C57BL/6 and CBA/J) mice by use of cDNA microarrays. By combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified a set of 69 genes that perfectly discriminated between mouse strains and between CM-R and CM-S mice. The analysis of gene ontological terms revealed that the genes that clustered and were related to susceptibility to CM preferentially belonged to some biological process classes, such as those pertaining to immune responses. Using a false discovery rate of 5% and the Welch t test, we identified 31 genes with consistent differential expression between CM-R and CM-S mice. These data indicate that microarray analysis may be useful for identification of candidate genes that are potentially responsible for resistance or susceptibility to mouse CM and suggest that candidate genes identified in mice could be specifically tested in humans for an association with disease severity.

Cerebral Malaria Pathogenesis

“…The findings of Lovegrove and colleagues 4 thus confirm the findings in the two previous murine CM microarray studies that IFN and IFN-regulating processes play a major role in murine CM pathogenesis. Interestingly, although earlier murine studies have implicated TNF-␣ in CM pathogenesis, 10 and TNF-related or TNF-induced genes were among the genes up-regulated in CM-susceptible but not CM-resistant mice in the study by Delahaye and colleagues, 23 TNF-␣-related genes were not a major part of the interactome hubs in the study by Lovegrove and colleagues. 4 In contrast, neither any of the caspase genes nor Fas (Cd95) was noted to be up-regulated in the studies by Delahaye and colleagues 23 or Sexton and colleagues.…”

“…Interestingly, although earlier murine studies have implicated TNF-␣ in CM pathogenesis, 10 and TNF-related or TNF-induced genes were among the genes up-regulated in CM-susceptible but not CM-resistant mice in the study by Delahaye and colleagues, 23 TNF-␣-related genes were not a major part of the interactome hubs in the study by Lovegrove and colleagues. 4 In contrast, neither any of the caspase genes nor Fas (Cd95) was noted to be up-regulated in the studies by Delahaye and colleagues 23 or Sexton and colleagues. 22 The brain tissue microarray studies performed thus far in murine CM show a number of similarities and most strikingly point to IFN-regulating and IFN-regulated processes as critical to CM, but they also differ in their findings.…”

“…The study identified 28 genes for which expression differed strongly between the susceptible and resistant mice, regardless of strain, but also identified several genes for which expression differed between the two different susceptible strains or the two different resistant strains. 23 The majority of genes that differed in level of expression between CM-susceptible and CM-resistant mice in the study by Delahaye and colleagues 23 were not "hub" genes in the interactome described by Lovegrove and colleagues, 4 but IFN-regulating genes were an important component of both gene expression sets. The findings of Lovegrove and colleagues 4 thus confirm the findings in the two previous murine CM microarray studies that IFN and IFN-regulating processes play a major role in murine CM pathogenesis.…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…cDNA microarray analysis from brain tissue performed in genetically resistant (CM-R) and susceptible (CM-S) mice identified 327 genes discriminated between infection stages, mouse strains and CM-R and CM-S phenotypes (Delahaye, Coltel et al 2006;Delahaye, Coltel et al 2007). Analysis of these 327 genes using expression analysis systematic explorer (EASE) software revealed that the clustered genes were biologically relevant to the defense response such as the response to malaria, inflammatory and immune response, and metabolism like oxidative phosphorylation, glycolysis/gluconeogenesis or tryptophan metabolism.…”

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

“…2 Transcript profiling experiments have documented a substantial pro-inflammatory response that is more pronounced in susceptible mice. [7][8][9] In addition, loss-of-function mutations in genes coding for pro-inflammatory molecules such as interferon-g (Ifng), lymphotoxin (Lta), hemolytic complement (C5a) and interferon regulatory factor 1 (Irf1) have been shown to protect against CM. [10][11][12][13] These observations support the hypothesis of for a central function for immune-mediated pathology in CM, with T cells, platelets and resident macrophages implicated in inflammatory response and tissue injury.…”