Early cellular sensing of blood stage Plasmodium Parasites by Innate Immune Cells

先天免疫细胞对血液阶段疟原虫寄生虫的早期细胞感知

基本信息

批准号：
9292250
负责人：
Gregoire Stephane Lauvau
金额：
$ 20.88万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-09 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292250
关键词：
Adult Antigen-Presenting Cells B-Lymphocytes Blood Bone Marrow Brain Injuries CD14 gene CD4 Positive T Lymphocytes Cells Cerebral Malaria Child Clinical Clinical Research Complex DNA Data Data Reporting Dendritic Cells Dendritic cell activation Disease Disease Outcome Effector Cell Erythrocytes Event Exhibits Experimental Models Genes Goals Human Immune Immune Cell Activation Immune response Immune system Immunity Impairment Infection Inflammatory Interferon Type I Interferon-alpha Interferons Kinetics Knowledge Longitudinal Studies Malaria Mediating Modeling Molecular Morbidity - disease rate Mus Natural Killer Cells Nucleic Acids Outcome Parasites Parasitic infection Pathogenesis Pathway interactions Patients Phagocytosis Plasmodium Plasmodium falciparum Plasmodium yoelii Play Process Production Public Health RNA RNA Helicase Reporting Resistance Rodent Rodent Model Role Severities Severity of illness Signal Transduction Source Symptoms T-Lymphocyte TLR7 gene TNF gene Tissues Toll-like receptors Vaccines Viral arm base cell type cytokine design experimental study immune activation immunoregulation in vivo insight loss of function macrophage malaria infection microbial monocyte mortality mouse model novel novel strategies nucleic acid detection pathogen prevent response sensor stem type I interferon receptor virtual

项目摘要

Abstract Malaria remains a great public health challenge and is one of the most deadly human parasitic infections. Despite this, the human immune response to Plasmodium infection is not well understood. Further, the contribution of host versus parasite factors to disease pathogenesis is controversial. These major gaps in knowledge have thwarted efforts to develop vaccines and strategies that modulate the human immune response to malaria infection and prevent serious sequelae. While clinical studies during natural infection can provide insight into host responses, experimental models such as the Plasmodium yoelii (Py), P. berghei (Pb) or P. chabaudi (Pc) rodent models are truly instrumental to define underlying mechanisms. For instance, both in these models and in humans, key cytokines such as interferons (IFNs) play essential roles. Recent studies and our preliminary data report a type I IFN signature response during Plasmodium falciparum (Pf) infection in infected children and adults who manifest mild and severe disease. Both in the Pb experimental cerebral malaria (CM) and the Py YM (17X) mouse models, lack of type I IFN production or signaling protects mice from lethal infection, establishing that type I IFN is a key contributor to severe disease outcomes. Thus, in humans as well as in rodent models, type I IFN plays a significant role in the pathogenesis of malaria infections. Production of type I IFN is initiated upon recognition of pathogen-derived nucleic acid motifs by innate immune sensors including Toll-like receptors (TLR7, TLR9), RNA helicases (Mda5/MAVS), and the stimulator of interferon genes (STING). While Mda5 can mediate type I IFN production in all cell types, the TLR- and the STING- pathways are activated in antigen-presenting cells (APCs). Plasmodium-derived nucleic acids, specifically RNA, CpG and AT-rich DNA stem-loop motifs are sensed via all of the major pathways above, which support the idea that Plasmodium parasites do induce potent type I IFN responses. However, which cell types produce bioactive type I IFN during blood stage malaria in vivo, through which molecular sensing mechanisms, and in which tissues is virtually unknown. Given that type I IFN signatures are heavily noted in humans and its impact in various surrogate mouse models of blood stage malaria, these questions are highly relevant to understanding the pathogenesis of this stage of the infection, and potential therapies. The goal of this project is to explore these mechanisms and how this relates to severity of malaria.

抽象的疟疾仍然是一个巨大的公共卫生挑战，是人类最致命的寄生虫感染之一。尽管如此，人类对疟原虫感染的免疫响应尚不清楚。此外，宿主与寄生虫因子对疾病发病机理的贡献是有争议的。这些主要差距知识阻碍了制定调节人免疫的疫苗和策略的努力对疟疾感染的反应并预防严重的后遗症。而自然感染期间的临床研究可以提供有关宿主反应的洞察力，即实验模型，例如疟原虫（Py），P。Berghei（PB）或P. chabaudi（PC）啮齿动物模型确实有助于定义潜在机制。例如，两者在这些模型和人类中，关键的细胞因子（例如干扰素（IFN））扮演着重要的角色。最近的研究我们的初步数据报告了恶性疟原虫（PF）感染期间I型IFN签名反应表现出轻度和重度疾病的感染儿童和成人。两者在PB实验大脑中疟疾（CM）和PY YM（17倍）小鼠模型，缺乏I型IFN产生或信号传导可保护小鼠免受致命感染，确定I型IFN是严重疾病结果的关键因素。那在人类中以及在啮齿动物模型中，I型IFN在疟疾感染的发病机理中起着重要作用。 IFN型的产生是在识别先天性衍生的核酸基准后开始的免疫传感器，包括收费受体（TLR7，TLR9），RNA解旋酶（MDA5/MAV）和刺激剂干扰素基因（刺）。虽然MDA5可以介导所有细胞类型中的I型IFN产生，但TLR-和在抗原呈递细胞（APC）中激活刺激途径。疟原虫衍生的核酸，特异性RNA，CpG和富含DNA的DNA茎环基序是通过上述所有主要途径感测的这支持疟原虫确实会影响潜在的I型IFN反应的想法。但是，哪个细胞类型在体内血液阶段疟疾期间产生生物活性I型IFN，分子感觉通过机制，其中组织几乎是未知的。鉴于该类型I IFN签名已大量注意到人类及其在各种替代老鼠的血液阶段疟疾模型中的影响，这些问题很高与理解感染这一阶段的发病机理以及潜在疗法有关。目标该项目是探索这些机制以及与疟疾严重程度的关系。