Malaria Host Pathogen Center Experiment 07A and 07B - Macaca fascicularis infected with Plasmodium knowlesi to produce and integrate clinical, hematological, parasitological, omics, telemetric and histopathological measures of acute primary infection.

This project is part of the Malaria Host-Pathogen Interaction Center (MaHPIC) - a transdisciplinary malaria systems biology research program initially supported by an NIH/NIAID contract (# HHSN272201200031C, 2012-2017; see http://www.systemsbiology.emory.edu). The MaHPIC has continued with support from the Defense Advanced Research Project Agency (DARPA) and others. The MaHPIC generates many data types (e.g., clinical, hematological, parasitological, metabolomics, functional genomics, lipidomics, proteomics, immune response, telemetry) and mathematical models, to iteratively test and develop hypotheses related to the complex host-parasite dynamics in the course of malaria in non-human primates (NHPs), and metabolomics data via collaborations with investigators conducting clinical studies in malaria endemic countries, with the overarching goal of better understanding human disease, pathogenesis, and immunity. Curation and maintenance of all data and metadata are the responsibility of the MaHPIC. The E07 cohort was inoculated with freshly dissected P. knowlesi sporozoites on 11/01/16. However, for unexplained reasons blood-stage parasitemias did not occur. Consequently, the E07 cohort was reinoculated with cryopreserved P. knowlesi sporozoites. This inoculation was performed on 1/20/17. Hence 'E07A' refers to samples and results from the failed inoculation from 11/01/16 and 'E07B' refers to samples and results from the successful inoculation on 1/20/17). Telemetry devices (DSI, model L11) with blood pressure sensors and electrocardiogram (ECG) leads were surgically implanted in seven malaria-naive male long-tailed macaques (Macaca fascicularis), approximately five years of age. After a resting period of three weeks, the telemetry implants were turned on and physiological data that include activity, temperature, ECG, and blood pressure were continuously collected. After the E07A failed infection using a fresh preparation of salivary gland sporozoites, the implants were deactivated to preserve battery life. Between E07A and E07B, a single rhesus macaque (M. mulatta) was added to the cohort as an infection control with no telemetry implant. At the start of E07B, telemetry implants were reactivated. Ten days after reactivation all animals were inoculated intravenously with cryopreserved P. knowlesi Malayan strain salivary gland sporozoites, obtained from Anopheles dirus infected with parasites from the Pk1A+ clone and previously tested in E30 for their infectivity of macaques. The sporozoite stocks used were produced, isolated and cryopreserved at the Centers for Disease Control and Prevention, and then stored at Yerkes. After inoculation, the macaques were profiled for clinical, hematological, parasitological, immunological, functional genomic, proteomic, and metabolomic measurements. The experiment was designed with pathology studies and thus terminal necropsies, which were scheduled at the log phase of the infection, at the peak of parasitemias, at the middle of the chronic phase, or at the end of the follow-up period of 45 days after the inoculation of the sporozoites. Capillary blood samples were collected daily for the measurement of complete blood counts (CBCs), reticulocytes, and parasitemias. Capillary blood samples were collected every other day to obtain plasma for metabolomic analysis. Venous blood and bone marrow samples were collected at six time points for functional genomic, targeted proteomic, targeted metabolomics, and immunological analyses. Physiological data noted above were continuously captured via telemetry. Within the MaHPIC, this project is known as ‘Experiment 07 (E07A and 07B)’. This dataset was produced by Dr. Steven E. Bosinger, Nirav Patel, and Gregory K Tharp at the Emory University Yerkes Genomics Core. To access other publicly available results from ‘E07' and other MaHPIC Experiments, including clinical results (specifics on drugs administered, diet, and veterinary interventions), and other omics, visit http://plasmodb.org/plasmo/mahpic.jsp . This page will be updated as datasets are released to the public. The experimental design and protocols for this study were approved by the Emory University Institutional Animal Care and Use Committee (IACUC) and the MRMC Office of Research Protection Animal Care and Use Review Office (ACURO). This dataset contains results from both E07A and E07B.

本项目隶属于疟疾宿主-病原体相互作用中心（Malaria Host-Pathogen Interaction Center，MaHPIC）——这是一项跨学科的疟疾系统生物学研究计划，最初由美国国立卫生研究院/美国国家过敏和传染病研究所（National Institutes of Health / National Institute of Allergy and Infectious Diseases）合同资助（编号HHSN272201200031C，资助周期2012-2017年；详情见http://www.systemsbiology.emory.edu）。此后，MaHPIC得到了美国国防高级研究计划局（Defense Advanced Research Projects Agency, DARPA）等机构的持续资助。MaHPIC生成多种类型的数据（涵盖临床、血液学、寄生虫学、代谢组学、功能基因组学、脂质组学、蛋白质组学、免疫应答、遥测数据等）与数学模型，用于反复验证并构建与非人灵长类（non-human primates, NHPs）疟疾感染过程中复杂宿主-寄生虫动态相关的假说；同时通过与疟疾流行地区开展临床研究的研究者合作，获取代谢组学数据，其核心目标是深入解析人类疟疾的发病机制、病理过程与免疫机制。所有数据与元数据的整理与维护工作均由MaHPIC负责。E07队列于2016年11月1日接种了新鲜解剖的诺氏疟原虫（Plasmodium knowlesi）子孢子，但由于不明原因未出现血液期虫血症。因此，研究团队于2017年1月20日对E07队列重新接种了冻存的诺氏疟原虫子孢子。其中，"E07A"指代2016年11月1日失败的首次接种对应的样本与实验结果，"E07B"指代2017年1月20日成功接种对应的样本与实验结果。研究团队为7只疟疾阴性的雄性食蟹猴（Macaca fascicularis，年龄约5岁）手术植入了带有血压传感器与心电图（electrocardiogram, ECG）导联的遥测设备（DSI型号L11）。经过3周的恢复期后，遥测设备启动，持续采集活动度、体温、ECG与血压等生理数据。在E07A失败的新鲜唾液腺子孢子感染实验结束后，为节省电池电量，遥测设备被关闭。在E07A与E07B实验之间，研究团队向队列中加入了1只恒河猴（M. mulatta）作为无遥测植入的感染对照。E07B实验启动时，遥测设备重新激活。重新激活后第10天，所有受试动物经静脉接种了冻存的诺氏疟原虫马来株唾液腺子孢子：该子孢子株来源于感染Pk1A+克隆寄生虫的按蚊（Anopheles dirus），此前已在E30实验中验证了其对猕猴的感染性。该子孢子冻存株由美国疾病控制与预防中心（Centers for Disease Control and Prevention, CDC）制备、分离并冻存，随后转运至埃默里大学耶基斯国家灵长类研究中心保存。接种后，研究团队对猕猴开展了临床、血液学、寄生虫学、免疫学、功能基因组学、蛋白质组学与代谢组学相关检测。本实验设置了病理学研究环节，因此安排了终端安乐死解剖，解剖时间分别定于感染对数期、虫血症峰值期、慢性感染中期，或子孢子接种后45天的随访期终点。研究人员每日采集毛细血管血样，用于全血细胞计数（complete blood counts, CBCs）、网织红细胞计数与虫血症检测；每两日采集一次毛细血管血样，获取血浆用于代谢组学分析。在6个时间点采集静脉血与骨髓样本，用于功能基因组学、靶向蛋白质组学、靶向代谢组学与免疫学分析。前述生理数据通过遥测设备持续采集。在MaHPIC框架内，本项目被称为"实验07（E07A与E07B）"。本数据集由埃默里大学耶基斯基因组学核心实验室的Steven E. Bosinger博士、Nirav Patel与Gregory K Tharp共同构建。若需获取"E07"及其他MaHPIC实验的公开结果（包括临床结果、给药方案、饮食与兽医干预细节，以及其他组学数据），可访问http://plasmodb.org/plasmo/mahpic.jsp，该页面将随数据集的公开发布持续更新。本研究的实验设计与方案已通过埃默里大学机构动物护理与使用委员会（Institutional Animal Care and Use Committee, IACUC）与MRMC研究保护办公室动物护理与使用审查办公室（Animal Care and Use Review Office, ACURO）的伦理审批。本数据集包含E07A与E07B的全部实验结果。