Effects of latent infection of Toxoplasma gondii strains with different genotypes on mouse behavior and brain transcripts.

Abstract

Background: Toxoplasma gondii can cause severe damage to immunodeficient hosts, and also compromise brain structure and function in immunocompetent hosts during latent infection. In China, the two different isolates, Chinese I (ToxoDB#9) and Chinese III are dominant epidemic strains widely spreading in humans and domestic animals and can lead to latent infection in host brain tissues, but the comparison of their manipulation patterns and mechanisms remains unclear.

Methods: Tachyzoites of the TgWh6 (Wh6) strain and the TgCtLHG (LHG) strain were used for establishing in vitro infection models within mouse microglia BV2 cells, and the differences in their invasion and proliferation patterns were observed. C57BL/6 J mice were used to establish in vivo latent infection models. After behavioral tests, the differential expressed transcripts (DETs) of the infected and control animals' cerebral cortex were sequenced by Nanopore RNA-seq. Functional differences of DETs were analyzed by Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes enrichment analysis (KEGG), and protein-protein interaction (PPI) and cluster analysis. Expression of the key candidates were verified by quantitative polymerase chain reaction (qPCR).

Results: In our infection models, we found that Wh6 had more vigorous invasion and proliferation abilities in vitro, while LHG had a greater ability to form cysts in vivo. In the latent infection phase, behavioral changes, including spatial working memory, cognitive and motor abilities, and anxiety, were observed in both Wh6 and LHG infected mice; however, the LHG group showed more serious anxiety. Among DETs, genes related to major histocompatibility complex (MHC) class II molecules were significantly upregulated in the infected mice, while genes related to synaptic transmission and neurodegenerative diseases were downregulated in the infected groups. The downregulated DETs of Sept4, Kcng4, Unc13c, and Prkcg in the WH6 group, which are related to synaptic transmission, and Ndrg2 and Arc in the LHG group, which are related to neurodegenerative diseases, were selected to be the key candidates in the latent infection phase.

Conclusions: Compared with WH6, although LHG has a milder invasion ability, it can cause increased behavioral disorders in hosts. Genes related to synaptic transmission and neurodegenerative diseases may be the main causes of host mental and behavioral disorders.