Role of the cytosolic DNA sensor cGAS in malaria

 描述(申请人提供)：疟疾仍然是当今世界上最重要的传染病之一。2013年，世界卫生组织估计有1.95亿人感染了疟疾。每年，疟疾造成50万至120万人死亡，其中大部分是儿童。迄今为止，尽管前景看好，但最好的疟疾疫苗试验显示效果有限，尽管联合疗法和经杀虫剂处理的蚊帐明显减轻了全球疟疾负担，但还需要做更多的工作。疟疾的发病机制与先天免疫反应密切相关：1)限制寄生虫繁殖，2)适当处理抗原以实现获得性免疫，3)可导致严重酸中毒、危及生命的贫血和导致患者死亡的脑部疾病。先天免疫反应的后一个方面对人类患者来说是一个真正的威胁。疟疾寄生虫通过接触宿主白细胞和组织细胞上表达的生殖系编码的先天免疫受体来引发炎症反应。最近，我们发现疟疾还会在患者的血白细胞中引起I型干扰素(IFN)反应。两种寄生虫产品， DNA和血球蛋白不成比例地影响先天免疫反应。血球蛋白是非常重要的，因为它帮助寄生虫DNA通过宿主吞噬小体隔间(TLR9参与)，然后进入细胞质，因为它对吞噬小体膜的稳定性有影响。此外，疟原虫DNA是产生干扰素的有效触发因素。我们推测，疟疾感染触发了胞质DNA传感器环-GMP-AMP-合成酶(CGAS)，并诱导干扰素基因刺激物(STING)的第二信使2‘3’-cGAMP的产生，从而导致I型干扰素的产生。I型干扰素诱导成百上千个干扰素应答基因的表达，疟疾患者血液中强烈的干扰素基因信号可能通过重新编程吞噬细胞和其他先天免疫细胞的天然免疫效应功能而参与疟疾感染的发病机制。我们提出的研究将通过确定cGAS是否参与人类疾病来更好地定义疟疾驱动干扰素的机制，并可能导致新的治疗策略。

 DESCRIPTION (provided by applicant): Malaria remains one of the most important infectious diseases in the world today. In 2013 the WHO estimated that 195 million individuals were infected with malaria. Annually, malaria causes 0.5-1.2 million deaths, mostly children. To date, although promising, the best malaria vaccine trials have demonstrated limited efficacy, and while combination therapy and insecticide-treated bed nets have clearly reduced the global burden of malaria, much more needs to be done. The pathogenesis of malaria is intimately linked to the innate immune response which: 1) limits parasite reproduction, 2) is required for the proper processing of antigen in order to achieve acquired immunity and, 3) can be the cause of severe acidosis, life-threatening anemia and cerebral disease that causes death in patients. This latter aspect of the innate immune response represents a real threat to human patients. Malaria parasites elicit inflammatory responses by engaging germ-line encoded innate immune receptors expressed on host leukocytes and tissue cells. Recently we have found that malaria also elicits a type I interferon (IFN) response in patient blood leukocytes. Two parasite products, DNA and hemozoin, disproportionately affect the innate immune response. Hemozoin is very important both because it helps traffic parasite DNA through the host phagolysosomal compartment (where TLR9 is engaged), and then into the cytosol because of its effect on phagolysosomal membrane stability. Furthermore, plasmodial DNA is a potent trigger for IFN production. We hypothesize that malarial infection triggers the cytosolic DNA sensor cyclic-GMP-AMP-synthase (cGAS) and induces production of 2'3'-cGAMP, a second messenger for STimulator of Interferon Genes (STING), leading to type I IFN production. Type I IFNs induce the expression of hundreds of IFN-responsive genes and the strong IFN gene signature in the blood of malaria patients may contribute to the pathogenesis during malarial infection by reprogramming the innate immune effector function of phagocytes and other innate immune cells. Our proposed studies will better define the mechanisms by which malaria drives IFN by determining if cGAS is involved in human disease, and may lead to novel therapeutic strategies.