[论文解读] Immunity to Plasmodium knowlesi H strain malaria in olive baboons

Barasa Mustafa, Maamun Jenneby+3 more|arXiv (Cornell University)|Jan 16, 2012

Malaria Research and Control参考文献 14被引用 4

一句话总结

本研究调查了橄榄狒狒感染 *Plasmodium knowlesi* H株疟疾后的免疫反应，发现急性感染与促炎细胞因子（IFN-γ、TNF-α、IL-6）水平升高以及抗炎细胞因子（IL-10、IL-4、IL-12）和抗体（IgG、IgM）水平降低相关。研究结果确立了橄榄狒狒作为人类疟疾研究的可靠临床前模型，因其宿主免疫反应与人类具有免疫学上的相似性。

ABSTRACT

Malaria disease is a major global health and economic development threat. It results in approximately 2.7 million deaths annually. There is currently no vaccine that has been licensed for use against malaria. Studies in animal models, especially non-human primates can lead to the revelation of possible immunological mechanisms that can lead to protection or predisposition of the host to malaria. Plasmodium knowlesi, a simian and human malaria parasite, is an attractive experimental parasite for malaria research since it can infect olive baboons (Papio anubis), non-human primates that have similar host-pathogen interactions to humans. This study was carried out to determine host immunological profiles provoked in olive baboons during the course of an infection with Plasmodium knowlesi. A total of eight adult baboons were intravenously inoculated with overnight cultured blood stage P. knowlesi H strain parasites. Five of these baboons became acutely infected while the other three became chronically infected. The immunological basis of this dual outcome of the infection was determined by measuring circulating cytokine (T helper 1 and T helper 2) and antibody (immunoglobulin G and immunoglobulin M) responses elicited in the infected baboons on a weekly basis by Enzyme Linked Immunosorbent Assay (ELISA) for up to six weeks post infection. Generated data for the first time indicated that acute P. knowlesi malaria is accompanied by increased concentrations of interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha) and IL 6 and reduced levels of circulating interleukin 10 (IL 10), IL 4, IL 12, immunoglobulin G (IgG) and IgM in the baboon host. These results are largely agreeable with data from human studies, thereby increasing the relevance of the olive baboon - P. knowlesi experimental infection system for future malaria studies.

研究动机与目标

• 表征橄榄狒狒感染 *Plasmodium knowlesi* H株期间的宿主免疫学特征。
• 比较急性与慢性感染狒狒的免疫反应，以识别保护或疾病进展的相关因素。
• 评估橄榄狒狒-*P. knowlesi* 模型在人类疟疾免疫学中的转化相关性。
• 测量感染后T辅助1型（Th1）和T辅助2型（Th2）细胞因子及免疫球蛋白反应的动态变化。
• 评估该模型在未来抗疟疾疫苗和治疗药物开发中的潜力。

提出的方法

• 八只成年橄榄狒狒通过静脉注射接种 *P. knowlesi* H株血 stage 疟原虫。
• 自感染后每周采集血液样本，持续最多六周，以监测免疫参数。
• 采用酶联免疫吸附试验（ELISA）测定循环中细胞因子（IFN-γ、TNF-α、IL-6、IL-10、IL-4、IL-12）和抗体（IgG、IgM）的水平。
• 根据临床和寄生虫学结果，将动物分类为急性或慢性感染。
• 比较急性与慢性感染组的免疫反应，以识别免疫学差异。
• 分析数据以识别感染期间促炎与抗炎介质的变化模式。

实验结果

研究问题

• RQ1 橄榄狒狒在急性与慢性 *P. knowlesi* 感染期间，Th1与Th2细胞因子反应的动态变化如何？
• RQ2 感染 *P. knowlesi* H株后，IgG与IgM抗体水平随时间如何变化？
• RQ3 哪些免疫学差异可区分急性感染与慢性感染的狒狒？
• RQ4 该狒狒模型中的免疫谱在多大程度上与人类疟疾病人的表现相似？
• RQ5 橄榄狒狒-*P. knowlesi* 系统能否作为研究人类疟疾免疫反应的可靠临床前模型？

主要发现

• 橄榄狒狒急性 *P. knowlesi* 疟疾与干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平显著升高相关。
• 慢性感染与IL-6持续升高以及与急性期相比促炎细胞因子水平降低相关。
• 急性感染期间，免疫调节性白细胞介素-10（IL-10）的循环水平显著降低。
• 急性感染狒狒中观察到Th2细胞因子（包括IL-4和IL-12）显著减少。
• 急性感染期间，免疫球蛋白G（IgG）和免疫球蛋白M（IgM）的水平降低，提示体液免疫受到抑制。
• 急性感染狒狒的免疫学特征与人类疟疾患者观察到的模式高度相似，支持该模型的转化相关性。