Mitchell Andrew J, Hansen Anna M, Hee Leia, Ball Helen J, Potter Sarah M, Walker John C, Hunt Nicholas H
University of Sydney, Department of Pathology, Medical Foundation Building, 92-94 Parramatta Rd., Camperdown NSW 2042, Australia.
Infect Immun. 2005 Sep;73(9):5645-53. doi: 10.1128/IAI.73.9.5645-5653.2005.
Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. berghei K173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-gamma) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-gamma, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN-gamma production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN-gamma at 24 h p.i., in a manner similar to animals infected with P. berghei K173 alone. These coinfected mice failed to develop CM. In addition, in a low-dose P. berghei K173 infection model, protection from CM was associated with early production of IFN-gamma. Early IFN-gamma production was present in NK-cell-depleted, gammadelta-cell-depleted, and Jalpha281(-/-) (NKT-cell-deficient) mice but absent from beta2-microglobulin mice that had been infected with P. berghei K173. Taken together, the results suggest that the absence of a regulatory pathway involving IFN-gamma and CD8(+) T cells in P. berghei ANKA infection allows the development of cerebral immunopathology.
脑型疟疾（CM）是人类感染恶性疟原虫后一种不常见但严重的并发症。动物和人体研究表明，CM的发病机制是免疫介导的，但导致脑部病变的确切机制尚不清楚。在小鼠中，接种伯氏疟原虫ANKA后第6天会发生CM，而感染密切相关的菌株伯氏疟原虫K173则不会导致CM。感染伯氏疟原虫K173与接种后24小时血浆γ干扰素（IFN-γ）增加以及脾脏和肝脏中一系列细胞因子（IFN-γ、白细胞介素-10 [IL-10]和IL-12）以及免疫调节酶吲哚胺2,3-双加氧酶的mRNA增加有关。相比之下，伯氏疟原虫ANKA感染与接种后24小时细胞因子产生缺乏有关，但在接种后3至4天IFN-γ产生激增。当小鼠同时感染ANKA和K173时，它们会产生早期细胞因子反应，包括接种后24小时IFN-γ的爆发，其方式类似于仅感染伯氏疟原虫K173的动物。这些共同感染的小鼠未能发展为CM。此外，在低剂量伯氏疟原虫K173感染模型中，对CM的保护与IFN-γ的早期产生有关。早期IFN-γ产生存在于NK细胞耗竭、γδ细胞耗竭和Jα281(-/-)（NKT细胞缺陷）小鼠中，但在感染伯氏疟原虫K173的β2-微球蛋白小鼠中不存在。综上所述，结果表明伯氏疟原虫ANKA感染中缺乏涉及IFN-γ和CD8(+) T细胞的调节途径会导致脑部免疫病理学的发展。
