Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Brain Behav Immun. 2016 May;54:73-85. doi: 10.1016/j.bbi.2016.01.002. Epub 2016 Jan 4.
Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
疟原虫感染导致人类罹患严重疟疾，影响包括肝脏、脾脏和大脑在内的各种器官，导致高发病率和死亡率。小鼠中的伯氏疟原虫 ANKA（PbA）感染非常类似于人类脑型疟疾（CM）的许多方面；因此，该模型已被用于研究 CM 的发病机制。细胞因子信号转导抑制因子 2（SOCS2）是一种由细胞因子和激素诱导的细胞内蛋白，调节免疫反应、神经发育、神经发生和神经营养途径。然而，SOCS2 在 CM 中的作用尚不清楚。感染 PbA 的 SOCS2 基因敲除（SOCS2(-/-)）小鼠最初对感染具有抵抗力，脑内寄生虫减少，TNF、TGF-β、IL-12 和 IL-17 的产生减少。有趣的是，在感染后期，SOCS2(-/-)小鼠的寄生虫血症增加，Treg 细胞浸润减少，与脑内 Th1 和 Th17 细胞及其相关细胞因子 IL-17、IL-6 和 TGF-β水平升高有关。神经保护性神经营养因子如胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的水平也显著降低。此外，感染 SOCS2(-/-)小鼠大脑中的分子改变与焦虑相关的行为和认知障碍有关。从机制上讲，这些结果表明，PbA 感染的 SOCS2(-/-)小鼠中一氧化氮（NO）的产生增加，通过 l-NAME 抑制 NO 合成会导致存活率显著降低、寄生虫血症控制中断以及更明显的焦虑样行为。用 l-NAME 治疗也会使感染 SOCS2(-/-)小鼠脑内 Th1、Th7 和 Treg 细胞的水平转移到感染 WT 小鼠中观察到的背景水平，只有增加的 CD8(+)IFN(+)T 细胞和炎性单核细胞例外。这些结果表明，SOCS2 在 PbA 感染过程中发挥双重作用，在寄生虫复制的控制中有害，但在免疫反应和神经营养因子产生的调节中至关重要。在这里，我们提供了强有力的证据，证明 SOCS2 和 NO 之间存在着在 PbA 感染过程中协调免疫反应和发展 CM 的关键关系。
