Abstract

To examine the immune environment of chronic Toxoplasma gondii infection in the brain, the characteristics of infection-immunity (premunition) in infection with T. gondii strain ME49 were investigated for 12 weeks postinfection (PI). The results showed that neuronal cell death, microglia infiltration and activation, inflammatory and anti-inflammatory cytokine expression, Stat1 phosphorylation, and microglia activation and inflammatory gene transcripts related to M1 polarization in the brain were increased during the acute infection (AI) stage (within 6 weeks PI), suggesting that innate and cellular inflammatory response activation and neurodegeneration contributed to excessive inflammatory responses. However, these immune responses decreased during the chronic infection (CI) stage (over 6 weeks PI) with reductions in phosphorylated STAT1 (pSTAT1) and eosinophilic neurons. Notably, increases were observed in transcripts of T-cell exhaustion markers (TIM3, LAG3, KLRG1, etc.), suppressor of cytokines signaling 1 protein (SOCS1), inhibitory checkpoint molecules (PD-1 and PD-L1), and Arg1 from the AI stage (3 weeks PI), implying active immune intervention under the immune environment of M1 polarization of microglia and increases in inflammatory cytokine levels. However, when BV-2 microglia were stimulated with T. gondii lysate antigens (strain RH or ME49) in vitro, nitrite production increased and urea production decreased. Furthermore, when BV-2 cells were infected by T. gondii tachyzoites (strain RH or ME49) in vitro, nitric oxide synthase and COX-2 levels decreased, whereas Arg1 levels significantly increased. Moreover, Arg1 expression was higher in ME49 infection than in RH infection, whereas nitrite production was lower in ME49 infection than in RH infection. Accordingly, these results strongly suggest that immune triggering of T. gondii antigens induces M1 polarization and activation of microglia as well as increase NO production, whereas T. gondii infection induces the inhibition of harmful inflammatory responses, even with M1 polarization and activation of microglia and Th1 inflammatory responses, suggesting a host–parasite relationship through immune regulation during CI. This is a characteristic of infection immunity in infection with T. gondii in the central nervous system, and SOCS1, a negative regulator of toxoplasmic encephalitis, may play a role in the increase in Arg1 levels to suppress NO production.

Highlights

  • Toxoplasma gondii is an Apicomplexan pathogen of the central nervous system (CNS) [1]

  • To observe the neuronal cell damage caused by T. gondii infection, histopathologic changes in the hippocampal region were examined by Hematoxylin and Eosin (H&E) staining

  • This result suggests that neurodegeneration increases during the acute infection (AI) stage and decreases in the chronic infection (CI) stage (9 weeks PI), despite the presence of harmful signs in the brain tissue, such as activation of inflammatory microglia and continuity of T. gondii infection

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Summary

Introduction

Toxoplasma gondii is an Apicomplexan pathogen of the central nervous system (CNS) [1]. Human T. gondii infection generally occurs via ingestion of oocysts (an environmentally resistant form) released in cat feces or undercooked meat containing tissue cysts [1]. Bradyzoites and sporozoites released from cysts and oocysts invade intestinal cells, where they are converted to tachyzoites, which can be disseminated via the blood or lymphatic system to remote organs and can induce an acute infection (AI) or chronic infection (CI) [1]. Immune responses to T. gondii infection differ during the proliferative (acute) and dormant (chronic and latent) stages and are dependent on differences in phenotype, virulence, and clinical sequelae of the strains of the clonal lineages, such as the highly virulent strain RH (type I) and the avirulent strain ME49 (type II) [1,2,3]. The onset and progression of T. gondii encystation result from both intrinsic preprogramming within the parasite and the immune response of the host, which eventually help to maintain a CI [1]

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