Abstract
Toxoplasma gondii (T. gondii) is an obligate intracellular parasitic protozoan that can cause toxoplasmosis in humans and other endotherms. T. gondii can manipulate the host gene expression profile by interfering with miRNA expression, which is closely associated with the molecular mechanisms of T. gondii-induced brain injury. However, it is unclear how T. gondii manipulates the gene expression of central nervous system (CNS) cells through modulation of miRNA expression in vivo during acute and chronic infection. Therefore, high-throughput sequencing was used to investigate expression profiles of brain miRNAs at 10, 25, and 50 days post-infection (DPI) in pigs infected with the Chinese I genotype T. gondii strain in this study. Compared with the control group 87, 68, and 135 differentially expressed miRNAs (DEMs) were identified in the infected porcine brains at 10, 25, and 50 DPI, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that a large number significantly enriched GO terms and KEGG pathways were found, and were mostly associated with stimulus or immune response, signal transduction, cell death or apoptosis, metabolic processes, immune system or diseases, and cancers. miRNA–gene network analysis revealed that the crucial connecting nodes, including DEMs and their target genes, might have key roles in the interactions between porcine brain and T. gondii. These results suggest that the regulatory strategies of T. gondii are involved in the modulation of a variety of host cell signaling pathways and cellular processes, containing unfolded protein response (UPR), oxidative stress (OS), autophagy, apoptosis, tumorigenesis, and inflammatory responses, by interfering with the global miRNA expression profile of CNS cells, allowing parasites to persist in the host CNS cells and contribute to pathological damage of porcine brain. To our knowledge, this is the first report on miRNA expression profile in porcine brains during acute and chronic T. gondii infection in vivo. Our results provide new insights into the mechanisms underlying T. gondii-induced brain injury during different infection stages and novel targets for developing therapeutic agents against T. gondii.
Highlights
Toxoplasma gondii is an obligate intracellular parasitic protozoan that can cause toxoplasmosis in all endotherms, including humans
ICR mice inoculated with the purified tachyzoites used for parasite challenge in pigs exhibited the onset of toxoplasmosis at 3 days post-infection (DPI)
The expression patterns of numerous differentially expressed miRNAs (DEMs) homologs, including miR-142-3p, miR-142-5p, miR-146a-5p, miR-155-5p, let-7d-5p, miR-125a, miR-455-3p, and miR-17-5p, obtained from the porcine brain in this study, were similar to those miRNAs identified in mouse brains following acute and chronic T. gondii infection (Zhou et al, 2020). We suggest that these DEMs or DEM homologs induced by T. gondii serve as essential mediators in the brain response, but are not strictly host specific. miR-142-3p and miR-142-5p were identified as showing upregulated expression in the brain tissue of pigs following T. gondii infection at all time points. miR-142-3p reduces regulatory T cell (Treg) functions by limiting AC9 and cAMP production (Huang et al, 2009), and manages autophagy and thymic-derived regulatory T cell survival by regulating the autophagy gene ATG16L1 post transcriptionally (Zhai et al, 2014; Lu et al, 2018). miR-142-5p is usually associated with adaptive immune responses of the host in experimental malaria models (Judice et al, 2016)
Summary
Toxoplasma gondii is an obligate intracellular parasitic protozoan that can cause toxoplasmosis in all endotherms, including humans. T. gondii infection can impair learning and memory in rodents (Kannan et al, 2010), and is involved in neurodegenerative disorders in humans, including Alzheimer’s, Huntington, and Parkinson’s diseases (Miman et al, 2010; Kusbeci et al, 2011; Donley et al, 2016). Such evidence suggests that T. gondii-induced injury of the cells of the central nervous system (CNS) might have important roles in inducing the occurrence of other neuronal disorders. MiRNAs involved in host brain responses to T. gondii infection are important regulators of early parasite dissemination in the brain tissue (Cannella et al, 2014). The invasion of cyst-forming T. gondii can change the miRNA expression of host brain, to which the host attempts to respond using two tactics: marking proteins with “protein tags” and adaptation of immune-related systems (Xu et al, 2013)
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