Role of the cytosolic DNA sensor cGAS in malaria

胞质 DNA 传感器 cGAS 在疟疾中的作用

• 批准号: 9264979
• 负责人: Douglas T Golenbock
• 金额: $ 19.04万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-21 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264979
• 关键词: Acidosis; Acute; Address; Affect; Anemia; Beds; Biological Assay; Blood; CRISPR/Cas technology; Cause of Death; Cells; Cerebral Edema; Cerebrum; Cessation of life; Child; Colombian; Combined Modality Therapy; Communicable Diseases; Complex; Cyclic GMP; Cytokine Gene; Cytosol; DNA; DNA Binding; DNA receptor; Dinucleoside Phosphates; Disease; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Enzymes; Fever; Gene Activation; Gene Expression; Generations; Genes; Germ Lines; Human; IRF3 gene; Immune; Immune system; Immunologic Receptors; Individual; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Insecticides; Interferon Type I; Interferon-alpha; Interferons; Lead; Leukocytes; Life; Link; Malaria; Malaria Vaccines; Measures; Membrane; Messenger RNA; Monitor; One-Step dentin bonding system; Parasites; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Periodicity; Phagocytes; Phagocytosis; Phagolysosome; Phosphorylation; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Production; Protein Secretion; RNA; Reporter; Reproduction; Role; Sampling; Second Messenger Systems; Series; Shapes; Signal Transduction; Surface; System; Technology; Time; Tissues; UMOD gene; Vaccines; acquired immunity; antigen processing; combat; cytokine; gene induction; genetic signature; hemozoin; human disease; improved; macrophage; malaria infection; mental state; microbial; monocyte; nano-string; novel therapeutic intervention; novel therapeutics; pathogen; peripheral blood; postcapillary venule; prevent; programs; public health relevance; response; sensor; uptake; vaccine trial

 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.

 描述（由申请人提供）：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1.95亿人感染疟疾。疟疾每年造成50万至120万人死亡，其中大多数是儿童。迄今为止，最好的疟疾疫苗试验虽然有希望，但效果有限，虽然联合疗法和驱虫蚊帐明显减轻了疟疾的全球负担，但仍有许多工作要做。疟疾的发病机制与先天免疫反应密切相关，先天免疫反应：1）限制寄生虫繁殖，2）是正确处理抗原以实现获得性免疫所必需的，3）可能是导致患者死亡的严重酸中毒、危及生命的贫血和脑疾病的原因。先天性免疫应答的后一方面代表了对人类患者的真实的威胁。疟疾寄生虫通过接合在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，我们发现疟疾也激发患者血液白细胞中的I型干扰素（IFN）反应。两种寄生虫产品， DNA和疟原虫色素不成比例地影响先天免疫反应。疟原虫色素是非常重要的，因为它有助于运输寄生虫DNA通过宿主吞噬溶酶体隔室（其中TLR 9参与），然后进入胞质溶胶，因为它对吞噬溶酶体膜的稳定性的影响。此外，疟原虫DNA是IFN产生的有效触发剂。我们假设疟疾感染触发胞质DNA传感器环-GMP-AMP-合酶（cGAS）并诱导2 '3'-cGAMP（干扰素基因刺激因子（STING）的第二信使）的产生，导致I型IFN的产生。I型IFN诱导数百种IFN应答基因的表达，并且疟疾患者血液中的强IFN基因签名可能通过重编程吞噬细胞和其他先天免疫细胞的先天免疫效应子功能而促成疟疾感染期间的发病机制。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IFN的机制，并可能导致新的治疗策略。

项目成果

Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production.

• DOI: 10.1016/j.chom.2016.06.003
• 发表时间: 2016-07-13
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Andrade WA;Firon A;Schmidt T;Hornung V;Fitzgerald KA;Kurt-Jones EA;Trieu-Cuot P;Golenbock DT;Kaminski PA
• 通讯作者: Kaminski PA