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

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.

Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts

“…Studies have also found that CXCL10, a chemokine released by neurons after brain injury, activates microglia to promote the dissipation of innervated dendrites from the injury site; these effects were obliterated in CXCR3 knockout mice. Other chemokines that have been implicated in microglia activation include C-C chemokine receptor 2 (CCR2), CXC Chemokine Receptor 3 (CXCR3), and chemokine (C-X3-C motif) receptor 1 (CX3CR1) ( 51 ).…”

Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice

“…Amplifications were performed using an ABI 7700 Prism Sequence Detector (Bio-Rad, Hercules, CA, United States). The cycle threshold (Ct) values were normalized to the expression levels using the 2 −∆∆Ct method ( Kobayashi et al, 2019 ; Umeda et al, 2021 ). Glyceraldehyde-3-phosphate dehydrogenase ( Gapdh ) was used as the internal control gene after comparison with Actb using RefFinder ( Xie et al, 2012 ).…”

“…Also, an obvious role of the CXCR3 in controlling parasite replication during acute P. chabaudi AS infection has been reported ( Berretta et al, 2019 ). In cases of infection with Toxoplasma gondii , which is closely related to the intracellular protozoan parasite N. caninum , CXCR3 deficiency results in the loss of ability to control intestinal infection ( Cohen et al, 2013 ), increased brain parasite burden ( Umeda et al, 2021 ), and severe embryonic damage in a pregnant model ( Nishida et al, 2021 ).…”