基因组印记作为宿主抗疟疾感染关键防御作用的机制研究

Malaria is a disease that kills more than 1 million children annually. In endemic areas, some people die from malaria while others survive the infection. Obviously effort must be made to cut the economic and personal cost of this disease. However It has been realized that eradication of the parasite P. falciparum is an impossible task. Additionally, recent data on a phase III clinical trial for the malaria vaccine RTSS showed only 30% of protection on infants. To enhance the efficacy of the control of this deleterious disease, it will require an intimate knowledge of the host and the parasite biology. While much has been learnt about the parasite and some effort been spent on trying to understand the biology of the host response to malaria, we still only understand a small percentage of the interaction between the host and the parasite..Using a rodent model for malaria infection, we have discovered that the first generation progeny mice resulting from a cross between two inbred strains of mice (SJL/J and C3H/He) are differentially susceptible to the malaria parasite, depending on their parent of origin and regardless of their genders. Further investigations on these progeny have revealed a differential destruction of infected red blood cells in the spleen at an early stage in the course of the infection, although these mice are strictly genetically identical. Together, this suggests that the epigenetic mechanism of genomic imprinting could play a major role in determining the outcome of the malaria infection and could also impact on the efficacy of the preventive strategy in endemic areas. This proposal aims to uncover the molecular and functional mechanisms under the imprinted genes responsible for host protection to the malaria parasite.

疟疾的流行每年造成超过百万儿童的死亡，在流行地区对经济发展和个人生命财产安全带来严重影响。最近RTSS疟疾疫苗III期临床结果发现只有约百分之三十的婴幼儿受到保护，再次显示短期内根除疟原虫的流行非常困难。若想更有效地控制疟疾，需要更多地了解宿主和寄生虫的生物学特性。虽然关于寄生虫和宿主间相互作用的研究有很多，但对宿主和寄生虫间关键的相互作用知之甚少。通过小鼠疟疾模型发现，由两个近交系小鼠（SJL/J和C3H/He）杂交产生的第一代小鼠对疟疾有不同的易感性。此现象和小鼠性别无关，而由父母的品系所决定的。进一步研究发现，尽管这些小鼠在遗传背景上是相同的，它们脾脏中被感染的红细胞在疟疾感染早期却有不同的破坏程度。上述结果表明基因组印记的表观遗传机制在决定疟疾感染的临床表现中有重要作用，并可能影响流行地区所采用预防策略的效果。本研究的目的是揭示赋予宿主抗疟疾感染印记基因中的分子与功能机制。

疟疾每年导致超过100万儿童死亡。在疾病流行地区，一些人死于疟疾，而另一些人则在感染后幸存下来。因而消灭恶性疟原虫是一项极为艰巨的任务，必须努力降低疾病对经济和个人健康的影响。此外，疟疾疫苗RTSS的III期临床试验的最新数据显示其保护率非常有限。为了提高对这种疾病的控制效果，需要对宿主和寄生虫生物学相互作用有深入的了解。 .使用小鼠感染模型，我们发现由两种近交品系杂交产生的第一代小鼠对疟疾寄生虫的易感性不同，这主要取决于他们的亲本而与他们的性别无关。对这些子代的进一步研究表明，尽管这些小鼠的基因是相同的，但在感染过程的早期阶段，脾脏中的红细胞在感染后所受到的破坏程度不同。我们确定了100多个调控宿主控制疟疾感染的亲本特异性来源的表观遗传位点。生物信息学分析进一步聚焦到几个关键候选位点。在这些基因座中，CD44是正在研究的首选候选基因座之一。这些位点的功能表征研究结果表明：宿主通过免疫识别和溶血清除感染的红细胞抵抗疟疾感染。总之，这些现象表明在疟疾感染后，基因组印记的表观遗传机制可能在确定疾病程度方面发挥重要作用，也可能影响流行地区预防策略的有效性。该项目旨在揭示负责宿主对疟原虫感染进行保护的印记基因的分子和功能机制。