Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

Abstract

c Toxoplasma gondii is an obligate intracellular parasite that invades a wide range of vertebrate host cells. Chronic infections with T. gondii become established in the tissues of the central nervous system, where the parasites may directly or indirectly modulate neuronal function. However, the mechanisms underlying parasite-induced neuronal disorder in the brain remain unclear. This study evaluated host gene expression in mouse brain following infection with T. gondii. BALB/c mice were infected with the PLK strain, and after 32 days of infection, histopathological lesions in the frontal lobe were found to be more severe than in other areas of the brain. Total RNA extracted from infected and uninfected mouse brain samples was subjected to transcriptome analysis using RNA sequencing (RNA-seq). In the T. gondii-infected mice, 935 mouse brain genes were upregulated, whereas 12 genes were downregulated. GOstat analysis predicted that the upregulated genes were primarily involved in host immune responses and cell activation. Positive correlations were found between the numbers of parasites in the infected mouse brains and the expression levels of genes involved in host immune responses. In contrast, genes that had a negative correlation with parasite numbers were predicted to be involved in neurological functions, such as small-GTPase-mediated signal transduction and vesicle-mediated transport. Furthermore, differential gene expression was observed between mice exhibiting the clinical signs of toxoplasmosis and those that did not. Our findings may provide insights into the mechanisms underlying neurological changes during T. gondii infection.T oxoplasma gondii, an obligate intracellular parasite, invades a wide variety of cells in its vertebrate hosts. The disease caused by T. gondii is usually asymptomatic but can be severe in immunosuppressed individuals, and cyst reactivation causes toxoplasmic encephalitis in AIDS patients (1). In addition, infection of nonimmune women during pregnancy can lead to congenital infection, with hydrocephaly, microcephaly, or intracerebral calcifications occurring in the fetus (2).Systemic infection by the proliferating stage of the parasite, the tachyzoite, is efficiently controlled by the cellular immune response. However, the pathogen persists in its slowly replicating stage, the bradyzoite, in tissue cysts mainly within the muscle and brain. In chronic infections, parasites within neurons can directly cause neuronal death and atrophy of neuronal processes, while inflammation via production of nitric oxide (NO) and inflammatory cytokines from microglia or immune cells may contribute to the death of neighboring neurons (3). However, the mechanisms underlying parasite-induced neuronal disorder in the brain remain unclear.In mice and rats, the specificity of behavioral modifications induced by T. gondii has been examined across a broad range of behaviors that primarily concern anxiety and learned fear in these animals (4). Recently, it has been suggested that chronic infection with T...

Z-DNA Binding Protein Mediates Host Control of Toxoplasma gondii Infection

“…From this data set, host Z-DNA binding protein 1 (ZBP1) was shown to be highly abun-dant at acute and chronic time points compared to values in uninfected samples. ZBP1 also had a fold change difference of approximately 240 in a similar study in which T. gondii-infected mice were compared at 30 days postinfection to uninfected mice (12). Since its initial identification, ZBP1 has been implicated in the cytosolic sensing of foreign bacterial and viral DNA and subsequent activation of type I interferon pathways (13)(14)(15).…”

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala

“…However, another study found that tissue cyst density in amygdalar areas (the medial and basolateral amygdala) is 2-fold higher than that in nonamygdalar areas (9), whereas the presence of tissue cysts in the forebrain contributes to the attenuation of predator odor aversion and anxiety-like behavior (16). Overall, these studies suggest that the T. gondii cyst distribution contributes to behavioral changes, but this still requires further investigation.Second, research on the mechanisms underlying behavioral changes following T. gondii infection has examined the effect of the infection on neuronal cell biology, including neurotransmitter synthesis, signal transduction, gene expression, and epigenetic modulation (14,(17)(18)(19)(20)(21). One study reported that dopaminergic cells are upregulated by infection, suggesting that T. gondii affects the central nervous system to manipulate host behavior (22).…”

Long-Term Relationships: the Complicated Interplay between the Host and the Developmental Stages of Toxoplasma gondii during Acute and Chronic Infections

“…More recent studies have used RNA-seq analysis to identify host and pathogen responses that may be important in the establishment and maintenance of chronic infection (98,138). Use of transcriptomic and proteomic analyses to address the host-pathogen interplay at distinct time points may be the best way to further elucidate the many unknown factors that contribute to persistence of T. gondii infection.…”

“…This reduces changes to the transcriptome that occur during sample preparation and allows for simultaneous analysis of host and pathogen transcriptomes. Using RNA-seq, studies have compared mouse brains that were uninfected or infected with T. gondii for 32 days (138). Another study performed a time course of the mouse forebrain infected with T. gondii for 10 days and 28 days postinfection.…”