Modification of dendritic cell function and priming of protective immunity by malaria blood-stage parasites

约有20亿人生活在疟疾有风险的地区。首次感染的儿童和幼稚的个人，通常是旅行者，死于恶性疟原虫感染的风险最大，据估计，每年有200万名3岁以下儿童死亡。生活在疟疾地区的幸存成年人在一系列感染后具有部分免疫力。目前尚不清楚这种保护性免疫，特别是细胞免疫是如何获得的，也不清楚为什么需要这么长时间才能形成。免疫学的最新进展表明，树突状细胞(DC)是有效诱导细胞免疫和启动记忆反应所必需的。树突状细胞吸收外来蛋白质，并将它们展示给T细胞，导致它们的激活。T细胞对于建立对疟疾的长期保护性免疫至关重要。然而，目前尚不清楚DC是否能感染疟疾寄生虫或感染疟疾的红细胞，并对它们进行处理，以激活保护性T细胞反应。我们的初步数据显示，人和小鼠的DC都能摄取寄生的红细胞，但红细胞表面的寄生虫衍生蛋白与DC受体的相互作用导致DC成熟缺陷。这一缺陷可能会阻碍自然疟疾感染期间T细胞的有效启动，从而导致疟疾流行区免疫功能的低下。鉴于这些新的基本发现，现在重要的是阐明：1)由寄生虫诱导的DC缺陷的性质2)评估这是否是所有疟原虫的共同特征，或者它是否可能与菌株毒力有关3)确定由缺陷DC诱导的疟疾特异性反应的性质和程度。了解寄生虫如何能够破坏免疫系统的一个关键诱导成分，对于在疟疾流行地区使用任何免疫疗法具有广泛的意义。

Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also unclear why it takes so long to develop. Recent advances in immunology have indicated that Dendritic Cells (DCs) are necesssary to induce effectively cellular immunity and prime memory responses. DCs take up foreign proteins and show them to T cells resulting in their activation. T cells are critical for the establishment of long-term protective immunity to malaria. However, it has not been known if DC can take up malaria parasites or malaria infected red-blood cells and process them to activate protective T cell responses. Our preliminary data shows that both human and mouse DC can take up parasitised red-cells, but that the interaction of parasite derived proteins on the surface of the red cell with DC receptors causes a defect in DC maturation. This defect may prevent effective priming of T cells during natural malaria infection, contributing to the poor development of immunity in malaria endemic areas. Given these novel fundamental findings, it is now important to elucidate: 1) The nature of the DC defect induced by the parasites 2) Assess whether this is a common feature of all Plasmodia, or whether it may relate to strain virulence 3) Determine the nature and extent of the malaria specific response induced by the defective DC. Understanding how parasites may be able to sabotage a critical inducing component of the immune system has wide implications for the use of any immuno-therapies in malaria endemic regions.