Transcriptomic Analysis of the Effects of Chemokine Receptor CXCR3 Deficiency on Immune Responses in the Mouse Brain during Toxoplasma gondii Infection.

Kousuke Umeda,Fumiaki Ihara,Youta Goto,Yutaka Suzuki,Nanako Ushio,Kenichi Watanabe,Ragab M Fereig,Sachi Tanaka,Yoshifumi Nishikawa

doi:10.3390/microorganisms9112340

Abstract

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals, including humans. We previously revealed through a whole-brain transcriptome analysis that infection with T. gondii in mice causes immune response-associated genes to be upregulated, for instance, chemokines and chemokine receptors such as CXC chemokine receptor 3 (CXCR3) and its ligand CXC chemokine ligand 10 (CXCL10). Here, we describe the effect of CXCR3 on responses against T. gondii infection in the mouse brain. In vivo assays using CXCR3-deficient mice showed that the absence of CXCR3 delayed the normal recovery of body weight and increased the brain parasite burden, suggesting that CXCR3 plays a role in the control of pathology in the brain, the site where chronic infection occurs. Therefore, to further analyze the function of CXCR3 in the brain, we profiled the gene expression patterns of primary astrocytes and microglia by RNA sequencing and subsequent analyses. CXCR3 deficiency impaired the normal upregulation of immune-related genes during T. gondii infection, in astrocytes and microglia alike. Collectively, our results suggest that the immune-related genes upregulated by CXCR3 perform a particular role in controlling pathology when the host is chronically infected with T. gondii in the brain.

Highlights

Toxoplasma gondii, an obligate intracellular parasite, infects a wide range of animals, including humans
For mice injected with 1000 tachyzoites, the parasite burden was significantly higher in the CXCR3KO mice than in the WT mice, while there was no significant difference (p > 0.05) for mice injected with 10,000 tachyzoites (Figure 1E,F)
As we aimed to investigate the effect of CXC chemokine receptor 3 (CXCR3) on the expression characteristics of genes during T. gondii infection, we focused on Differentially Expressed Genes (DEGs) whose upregulation during T. gondii infection was impaired by CXCR3-deficiency

Summary

Introduction

Toxoplasma gondii, an obligate intracellular parasite, infects a wide range of animals, including humans. The parasite has two different stages in its intermediate hosts: tachyzoites and bradyzoites. Tachyzoites are the fast-replicating parasite stage that occurs during acute infections, whereas bradyzoites are the slowly multiplying encysted stage present in host tissues during chronic latent infections. A major source of human infections arises from bradyzoite contamination of meat [1], and a third of the world’s population is reportedly chronically infected with this parasite [2]. Toxoplasmosis is generally asymptomatic in immunocompetent humans, but it causes severe clinical diseases in immunocompromised individuals and pregnant mothers and infants with congenital disorders [3]. Uncontrolled parasite replication (called toxoplasmic encephalitis) causes life-threatening brain damage, as characterized by brain abscesses and necrotic brain areas.

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