Microarray gene expression analysis reveals major differences between Toxocara canis and Toxocara cati neurotoxocarosis and involvement of T. canis in lipid biosynthetic processes

Abstract

Toxocara canis and Toxocara cati are globally occurring intestinal nematodes of dogs and cats with a high zoonotic potential. Migrating larvae in the CNS of paratenic hosts, including humans, may cause neurotoxocarosis resulting in a variety of neurological symptoms. Toxocara canis exhibits a stronger affinity to the CNS than T. cati, causing more severe neurological symptoms in the mouse model. Pathomechanisms of neurotoxocarosis as well as host responses towards the respective parasite are mostly unknown. Therefore, the aim of this study was to characterise the pathogenesis at a transcriptional level using whole genome microarray expression analysis and identify differences and similarities between T. canis- and T. cati-infected brains. Microarray analysis was conducted in cerebra and cerebella of infected C57Bl/6J mice 42daysp.i. revealing more differentially transcribed genes for T. canis- than T. cati-infected brains. In cerebra and cerebella of T. canis-infected mice, a total of 2304 and 1954 differentially transcribed genes, respectively, were identified whereas 113 and 760 differentially transcribed genes were determined in cerebra and cerebella of T. cati-infected mice. Functional annotation analysis revealed major differences in host responses in terms of significantly enriched biological modules. Up-regulated genes were mainly associated with the terms “immune and defence response”, “sensory perception” as well as “behaviour/taxis” retrieved from the Gene Ontology database. These observations indicate a strong immune response in both infection groups with T. cati-infected brains revealing less severe reactions. Down-regulated genes in T. canis-infected cerebra and cerebella revealed a significant enrichment for the Gene Ontology term “lipid/cholesterol biosynthetic process”. Cholesterol is a highly abundant and important component in the brain, representing several functions. Disturbances of synthesis as well as concentration changes may lead to dysfunction in signal transduction and neurodegenerative disease. Overall, only a minor overlap of differentially transcribed genes was observed between the two infection groups in both brain parts. Most genes are regulated individually in each infection group, supporting the evident differences of both roundworm species observed in the paratenic host in previous studies. In summary the present study underlines the differences in pathogenicity of T. canis and T. cati. It furthermore provides a comprehensive basis for future analyses over the course of infection as well as functional tests to identify gene regulatory circuits that are crucial for pathogenesis of neurotoxocarosis. The results of this study provide a promising foundation for further specific research to evaluate the particular pathogenetic mechanisms and to identify possible therapeutic targets.