Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

Invading pathogens trigger specific host responses, an understanding of which might identify genes that function in pathogen recognition and elimination. In this study, we performed trans-species expression quantitative trait locus (ts-eQTL) analysis using genotypes of the Plasmodium yoelii malaria parasite and phenotypes of mouse gene expression. We significantly linked 1,054 host genes to parasite genetic loci (LOD score ≥ 3.0). Using LOD score patterns, which produced results that differed from direct expression-level clustering, we grouped host genes that function in related pathways, allowing functional prediction of unknown genes. As a proof of principle, 14 of 15 randomly selected genes predicted to function in type I interferon (IFN-I) responses were experimentally validated using overexpression, small hairpin RNA knockdown, viral infection, and/or infection of knockout mice. This study demonstrates an effective strategy for studying gene function, establishes a functional gene database, and identifies regulators in IFN-I pathways. [Display omitted] •Trans-species eQTL links host gene expression to genetic loci of the malaria parasite•Genome-wide pattern of LOD score clusters together genes with similar functions•Databases of host gene clusters and linked parasite genetic loci are established•Predicted regulators of IFN-I responses are experimentally confirmed Wu et al. develop an approach to study pathogen-host genetic interactions by performing trans-species expression quantitative trait locus analysis. They use patterns of genome-wide LOD scores to cluster and predict gene functions. They verify their predictions by experimental confirmation of selected genes functioning in the type I interferon pathway.