Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria

Abstract

Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.

Comparative transcriptomics of aphid species that diverged > 22 MYA reveals genes that are important for the maintenance of their symbiosis

“…2 ; Supplemental Table 6 ). To determine which of these differentially expressed orthologs have the biggest effect in fold-change between bacteriocytes and body for both species similar to Korb et al 19 and Georgiadou et al 20 we conducted PCA where axis 1 and 2 explained ~ 53.3% and 46.7% of the variance in the data, respectively. The top 100 shared orthologs (70 were non-redundant between both axis 1 and 2) with the highest positive and negative correlations with principal components 1 and 2 consist of 25 up-regulated and 45 down-regulated orthologs (Fig.…”

“…To compare patterns of gene expression between species without species-specific variation, specifically focusing on genes associated with symbiosis that are differentially expressed in the bacteriocyte compared to body tissues, we conducted interspecies comparative transcriptomics analysis using PCA following the pipeline of Georgiadou et al 20 (see Supplemental Methods for detailed pipeline on interspecies transcriptomics analyses). Pcord (version 4.25) 52 was used for PCA analysis.…”

Gene expression analyses reveal differences in children’s response to malaria according to their age

“…This limitation (inherent to human field studies) could contribute to our observed differences in neutrophil and T cell proportions. Future work in animal models, where the infection and sampling times can be tightly controlled, could help to clarify the relationship between T cells and parasitemia, although important differences between animal models and human pathology exist ( 47 ).…”

The malarial blood transcriptome: translational applications

“…Selection of inappropriate animal models is one possible cause of promising drugs failing at human trial stage [ 70 ]. Recently, comparative transcriptomic approaches have been used to identify translationally relevant mouse models for different human malarial phenotypes including CM, SMA, and hyperlactatemia [ 71 ], reasoning that the transcriptome may reflect many of the biological processes associated with disease. This approach could be used to identify animal models in which there is concordance of biological processes relevant to the specific therapeutic target and treatment between the mouse model and human disease, maximising the chance that results from the mouse model will be translatable to humans.…”