Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Infect Immun. 2011 Apr;79(4):1750-8. doi: 10.1128/IAI.00810-10. Epub 2011 Jan 18.
Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-β) has been used in the treatment of diseases, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-β also limits disease progression in experimental cerebral malaria (ECM). Plasmodium berghei-infected mice treated with IFN-β died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-β did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-β administration. P. berghei infection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitized RBCs to the endothelial cell. In this article, we report that IFN-β treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-α). In addition, IFN-β-treated P. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-β has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.
脑型疟疾（CM）是恶性疟原虫感染的主要并发症，尤其在儿童中多见。脑型疟疾的发病机制涉及寄生红细胞（RBC）介导的血管炎症、免疫刺激、血脑屏障完整性丧失和脑毛细血管阻塞。因此，抑制血管炎症和免疫细胞募集对于限制疾病进程至关重要。β干扰素（IFN-β）已被用于治疗多发性硬化症（MS）等疾病，但尚未在脑型疟疾的治疗中进行探索。因此，我们试图确定 IFN-β是否也可以限制实验性脑型疟疾（ECM）的疾病进展。与感染的小鼠相比，用 IFN-β治疗的感染伯氏疟原虫的小鼠死亡较晚，存活率提高，并且血脑屏障功能得到改善。IFN-β并未改变全身寄生虫血症。然而，我们发现了多个被 IFN-β 给药修饰的作用部位。感染伯氏疟原虫导致脑血管内皮细胞中趋化因子（C-X-C 基序）配体 9（CXCL9）的表达增加，该趋化因子吸引 T 细胞进入大脑，同时也增加了 T 细胞趋化因子（C-X-C 基序）受体 3（CXCR3）的表达。感染还增加了细胞间黏附分子 1（ICAM-1）的细胞含量，ICAM-1 是寄生虫附着在内皮细胞上的重要分子。在本文中，我们报告称 IFN-β 治疗可导致大脑中 CXCL9 和 ICAM-1 减少、T 细胞 CXCR3 表达减少以及血清肿瘤坏死因子-α（TNF-α）下调。此外，IFN-β 治疗的感染伯氏疟原虫的小鼠脑内 T 细胞浸润也较少，进一步证明了其保护作用。因此，IFN-β 具有重要的抗炎特性，可改善 ECM 的严重程度并延长小鼠的存活时间。
