Laboratory of Biology of the Interactions, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
Multiuser Laboratory for Research Support in Nephrology and Medical Sciences, Federal University Fluminense, Niterói, Rio de Janeiro, Brazil.
PLoS One. 2021 Oct 5;16(10):e0258199. doi: 10.1371/journal.pone.0258199. eCollection 2021.
The Apicomplexa protozoan Toxoplasma gondii is a mandatory intracellular parasite and the causative agent of toxoplasmosis. This illness is of medical importance due to its high prevalence worldwide and may cause neurological alterations in immunocompromised persons. In chronically infected immunocompetent individuals, this parasite forms tissue cysts mainly in the brain. In addition, T. gondii infection has been related to mental illnesses such as schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, as well as mood, personality, and other behavioral changes. In the present study, we evaluated the kinetics of behavioral alterations in a model of chronic infection, assessing anxiety, depression and exploratory behavior, and their relationship with neuroinflammation and parasite cysts in brain tissue areas, blood-brain-barrier (BBB) integrity, and cytokine status in the brain and serum. Adult female C57BL/6 mice were infected by gavage with 5 cysts of the ME-49 type II T. gondii strain, and analyzed as independent groups at 30, 60 and 90 days postinfection (dpi). Anxiety, depressive-like behavior, and hyperactivity were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic T. gondii infection, in a direct association with the presence of parasite cysts and neuroinflammation, independently of the brain tissue areas, and linked to BBB disruption. These behavioral alterations paralleled the upregulation of expression of tumor necrosis factor (TNF) and CC-chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES) in the brain tissue. In addition, increased levels of interferon-gamma (IFNγ), TNF and CCL2/MCP-1 were detected in the peripheral blood, at 30 and 60 dpi. Our data suggest that the persistence of parasite cysts induces sustained neuroinflammation, and BBB disruption, thus allowing leakage of cytokines of circulating plasma into the brain tissue. Therefore, all these factors may contribute to behavioral changes (anxiety, depressive-like behavior, and hyperactivity) in chronic T. gondii infection.
刚地弓形虫是一种专性细胞内寄生的顶复门原虫，也是弓形体病的病原体。这种疾病具有重要的医学意义，因为它在全球范围内的发病率很高，并且可能导致免疫功能低下者的神经改变。在慢性感染的免疫功能正常的个体中，这种寄生虫主要在大脑中形成组织囊肿。此外，弓形体感染与精神疾病有关，如精神分裂症、双相情感障碍、抑郁症、强迫症，以及情绪、人格和其他行为变化。在本研究中，我们评估了慢性感染模型中行为改变的动力学，评估了焦虑、抑郁和探索行为，以及它们与脑组织中神经炎症和寄生虫囊肿、血脑屏障（BBB）完整性以及大脑和血清中细胞因子状态的关系。成年雌性 C57BL/6 小鼠通过灌胃感染 ME-49 型 II 型弓形虫 5 个囊肿，并在感染后 30、60 和 90 天分别作为独立组进行分析。在早期（30dpi）和长期（60 和 90dpi）慢性弓形虫感染中，检测到焦虑、抑郁样行为和多动，这与寄生虫囊肿和神经炎症的存在直接相关，与脑组织区域无关，与 BBB 破坏有关。这些行为改变与大脑组织中肿瘤坏死因子（TNF）和 CC 趋化因子（CCL2/MCP-1、CCL3/MIP-1α、CCL4/MIP-1β和 CCL5/RANTES）的表达上调平行。此外，在感染后 30 和 60 天，外周血中也检测到干扰素-γ（IFNγ）、TNF 和 CCL2/MCP-1 水平升高。我们的数据表明，寄生虫囊肿的持续存在会引起持续的神经炎症和 BBB 破坏，从而使循环血浆中的细胞因子漏入脑组织。因此，所有这些因素都可能导致慢性弓形虫感染中的行为改变（焦虑、抑郁样行为和多动）。
