[论文解读] Plasmodium knowlesi H strain pregnancy malaria immune responses in olive baboons (Papio anubis)

Barasa Mustafa, Mwangi Irungu Michael+4 more|arXiv (Cornell University)|Apr 14, 2012

Malaria Research and Control参考文献 9被引用 5

一句话总结

本研究利用控制性模型模拟人类妊娠疟疾，调查了自然感染 *Plasmodium knowlesi* H株的橄榄狒狒（Papio anubis）在妊娠期间的免疫反应。研究发现，妊娠疟疾与IFN-γ和IL-6反应受抑相关，而TNF-α则上调，与人类妊娠疟疾中观察到的关键免疫失调特征一致，验证了狒狒模型在转化研究中的适用性。

ABSTRACT

Approximately 24 million pregnant women in Sub-Saharan Africa are at risk of suffering from pregnancy malaria complications. Mechanisms responsible for increased susceptibility to malaria in pregnant women are not fully understood. Baboons are susceptible to Plasmodium knowlesi and their reproductive physiology and host pathogen interactions are similar to those in humans, making them attractive for development as a model for studying mechanisms underlying pregnancy malaria. This study exploited the susceptibility of baboons to Plasmodium knowlesi infection to characterize cytokine and peripheral blood mononuclear cell recall proliferation responses underlying the pathogenesis of pregnancy malaria in baboons infected with Plasmodium knowlesi. The pregnancies of three time mated adult female baboons and their gestational levels were confirmed by ultrasonography. On the 150th day of gestation, the pregnant baboons together with four non pregnant controls were infected with Plasmodium knowlesi H strain parasites. Collection of peripheral sera, and mononuclear cells was then done on a weekly basis. Sera cytokine concentrations were measured by Enzyme Linked Immunosorbent Assay (ELISA) using respective enzyme conjugated antibodies. Peripheral blood mononuclear cell recall proliferation assays were also done on a weekly basis. Results indicate that pregnancy malaria in this model is associated with suppression of interferon gamma and interleukin 6 (IL-6) responses. Tumour necrosis factor alpha responses were upregulated while IL-4, IL-12 and recall proliferation responses were not different from controls. These data to a great extent are consistent with some findings from human studies, showing the feasibility of this model for studying mechanisms underlying pregnancy malaria.

研究动机与目标

• 开发一种非人灵长类动物模型，利用 *Plasmodium knowlesi* H株在橄榄狒狒中研究妊娠疟疾病理机制。
• 表征感染 *P. knowlesi* 的妊娠与非妊娠狒狒的细胞因子谱及T细胞回忆反应。
• 通过与人类妊娠疟疾中报道的免疫反应进行比较，评估狒狒模型的转化研究相关性。

提出的方法

• 三只妊娠期配对的雌性橄榄狒狒和四只非妊娠对照组在妊娠第150天感染 *Plasmodium knowlesi* H株。
• 感染后每周采集外周血样本，通过酶联抗体的ELISA方法检测血清细胞因子。
• 每周分离外周血单个核细胞（PBMCs）进行抗原特异性回忆增殖试验。
• 感染前通过超声波检查确认妊娠状态和妊娠周期。
• 定量比较妊娠组与非妊娠组中IFN-γ、IL-4、IL-6、IL-12和TNF-α的细胞因子浓度。
• 对免疫反应随时间的变化进行统计比较，识别促炎与抗炎细胞因子动态的关键差异。

实验结果

研究问题

• RQ1 感染 *Plasmodium knowlesi* H株的妊娠与非妊娠橄榄狒狒在细胞因子反应上存在何种差异？
• RQ2 妊娠与非妊娠感染狒狒的T细胞回忆增殖反应在多大程度上存在差异？
• RQ3 本研究中观察到的免疫反应是否与人类妊娠疟疾中报道的反应一致？

主要发现

• 与非妊娠对照组相比，橄榄狒狒妊娠疟疾与干扰素-γ（IFN-γ）反应显著受抑相关。
• 妊娠动物的白介素-6（IL-6）反应亦被抑制，提示促炎反应减弱。
• 肿瘤坏死因子-α（TNF-α）水平在妊娠狒狒中上调，提示先天免疫激活增强。
• 妊娠组与非妊娠组在IL-4或IL-12反应方面未观察到显著差异。
• 与对照组相比，妊娠狒狒的抗原特异性T细胞回忆增殖反应无显著变化。
• 总体而言，该模型的免疫谱与人类妊娠疟疾中观察到的关键免疫特征高度一致，支持其作为临床前模型的有效性。