ABSTRACT

Toxoplasmosis is a zoonotic disease of major significant perspectives in public health and veterinary medicine. So far, the available drugs control only the active infection, once the parasite encysts in the tissues, they lose their efficacy. Cytokines; IFN-γ and IL-10, play a critical role in the modulation of toxoplasmic encephalitis and neuro-inflammation in chronic toxoplasmosis. Antiretroviral protease inhibitors applied in the treatment of acquired immunodeficiency syndrome, revealed activity against multiple parasites. Aluvia (lopinavir/ritonavir) (L/R); an aspartyl protease inhibitor, had efficiently treated T. gondii RH strain infection. We investigated the potential activity of L/R against experimental T. gondii infection with a cystogenic Me49 strain in mice, considering the role of IFN-γ and IL-10 in the neuropathology versus pyrimethamine-sulfadiazine combination therapy. Three aluvia regimens were applied; starting on the day of infection (acute phase), 2-week PI (early chronic phase) and eight weeks PI (late chronic phase). L/R reduced the brain-tissue cyst burden significantly in all treatment regimens. It impaired the parasite infectivity markedly in the late chronic phase. Ultrastructural changes were detected in Toxoplasma cyst membrane and wall, bradyzoite membrane and nuclear envelope. The signs of bradyzoite paraptosis and cytoplasmic lipid droplets were observed. L/R had significantly reduced the brain-homogenate levels of IFN-γ and IL-10 in its three regimens however, they could not reach the normal level in chronic phases. Cerebral hypercellularity, perivascular inflammatory response, lymphoplasmacytic infiltrates and glial cellular reaction were ameliorated by L/R treatment. Herein, L/R was proved to possess promising preventive and therapeutic perspectives in chronic cerebral toxoplasmosis.

摘要

弓形虫病是一种在公共卫生和兽医学中具有重要意义的人畜共患病。到目前为止，现有的药物只能控制活动性感染，一旦寄生虫包囊进入组织，它们就会失去功效。细胞因子；IFN-γ 和 IL-10 在慢性弓形虫病的弓形虫脑炎和神经炎症的调节中起关键作用。用于治疗获得性免疫缺陷综合征的抗逆转录病毒蛋白酶抑制剂显示出对多种寄生虫的活性。Aluvia（洛匹那韦/利托那韦）（L/R）；一种天冬氨酰蛋白酶抑制剂，可有效治疗刚地弓形虫RH 菌株感染。我们研究了 L/R 对实验性弓形虫的潜在活性考虑到 IFN-γ 和 IL-10 在神经病理学与乙胺嘧啶-磺胺嘧啶联合治疗中的作用，小鼠感染囊性 Me49 菌株。应用了三种 aluvia 方案；从感染当天开始（急性期）、2 周 PI（早期慢性期）和 8 周 PI（晚期慢性期）。在所有治疗方案中，L/R 显着降低了脑组织囊肿负担。它在慢性晚期显着损害了寄生虫的传染性。在弓形虫中检测到超微结构变化囊膜和壁，缓殖子膜和核包膜。观察到缓殖子垂体和细胞质脂滴的迹象。L/R 在其三种方案中显着降低了脑匀浆 IFN-γ 和 IL-10 的水平，然而，它们在慢性期无法达到正常水平。L/R 治疗可改善脑细胞增多、血管周围炎症反应、淋巴浆细胞浸润和神经胶质细胞反应。在此，L/R 被证明在慢性脑弓形虫病中具有良好的预防和治疗前景。