Integrative whole-transcriptome analysis of circRNAs, lncRNAs, miRNAs, and mRNAs reveals regulatory networks in mouse brain during Toxoplasma gondii infection.

Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is a zoonotic parasite that infects humans and animals worldwide. Although RNAs contribute to many vital biological processes within the central nervous system, their involvement in T. gondii infection remains poorly understood. In this study, we investigated the differential expression of three types of noncoding RNAs and mRNAs in the brain tissues of mice orally infected with 20 cysts of T. gondii Pru strain per mouse during the acute and chronic phases of infection. We used RNA sequencing (RNA-seq) to comprehensively profile the differentially expressed circular RNAs (DEcircRNAs), long noncoding RNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs) in mouse brain tissue at both stages of infection. Acute infection was associated with alterations in 14 circRNAs, 427 lncRNAs, 105 miRNAs, and 1490 mRNAs. In the chronic phase, 17 circRNAs, 581 lncRNAs, 131 miRNAs, and 2646 mRNAs were differentially expressed. Importantly, 36 miRNAs and 782 mRNAs were dysregulated at both phases. Pathway enrichment analysis revealed that the acute phase was associated with autophagy and the PI3K-Akt signaling pathway, while chronic infection was enriched for neurotrophin and MAPK signaling pathways. Additionally, we constructed competitive endogenous RNA (ceRNA) networks to elucidate the complex regulatory interactions among DEcircRNAs, DElncRNAs, and DEmiRNAs that may modulate the host's transcriptional response to T. gondii. The discovery of DE circRNAs, lncRNAs, miRNAs, and mRNAs that mediates the brain response to T. gondii infection reveals an additional layer of regulation of T. gondii infection of the murine brain.