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Infection of mice with strains of  Plasmodium yoelii  parasites can result in different pathology, but molecular mechanisms to explain this variation are unclear. Here we show that a  P .  yoelii  gene encoding a HECT-like E3 ubiquitin ligase ( Pyheul ) influences parasitemia and host mortality. We genetically cross two lethal parasites with distinct disease phenotypes, and identify 43 genetically diverse progeny by typing with microsatellites and 9230 single-nucleotide polymorphisms. A genome-wide quantitative trait loci scan links parasite growth and host mortality to two major loci on chromosomes 1 and 7 with LOD (logarithm of the odds) scores = 6.1 and 8.1, respectively. Allelic exchange of partial sequences of  Pyheul  in the chromosome 7 locus and modification of the gene expression alter parasite growth and host mortality. This study identifies a gene that may have a function in parasite growth, virulence, and host–parasite interaction, and therefore could be a target for drug or vaccine development.

A Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence