Project 1 Viral Genomics: surveillance, epidemiology, host response, and viral immunogenicity

项目 1 病毒基因组学：监测、流行病学、宿主反应和病毒免疫原性

• 批准号: 10687980
• 负责人: Daniel E Neafsey
• 金额: $ 68.18万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687980
• 关键词: Project; Viral; Genomics; surveillance; epidemiology

Ensuring a world safe from microbial threats remains a pressing challenge. However, significant gaps remain in our understanding of viral diseases. This proposal employs genomics to address these three major needs: Genomic detection and epidemiology of emerging viral threats in humans and vectors. For emerging viruses, such as Lassa, Ebola, Zika, Powassan, and other NIAID Category A-C Priority Pathogens, the natural prevalence, evolution, genetic diversity, and transmission among and between humans and zoonotic hosts are not well characterized, which threatens our ability to prepare for and even identify human cases when they occur. Pathogen genomics provides critical public health insight into the movement of viral threats. In partnership with established clinical, public health, and academic collaborators in West Africa and Massachusetts, this project will sequence viruses both human patients and zoonotic reservoirs (African rodents, American ticks and mosquitoes), publicly distribute genomic and metagenomic datasets, and rapidly deliver analyses relevant to the evolution, epidemiology and ecology of these viruses, with a focus on insights that may inform the ongoing development work of diagnostics, therapeutics, and other intervention strategies. Tissue-specific and single-cell characterizations of host response and viral dynamics during viral hemorrhagic fever infection. Viral hemorrhagic fevers (VHFs) like Ebola and Lassa are highly fatal, but how the molecular and cellular host response mechanisms differ between fatal and non-fatal cases is poorly understood. In partnership with NIAID’s Integrated Research Facility in Frederick, MD (BSL-4), this project will sequence in vivo VHF infections in animal model organisms, simultaneously profiling both the host transcriptional response and viral replication and evolution within different host tissues, and utilizing single-cell RNA-seq approaches to interrogate individual host PBMC types. This will provide a new understanding of cell-specific host response to VHF infections, with insights into the differing mechanisms behind fatality and recovery and inform the development of countermeasures for VHFs. Systematic discovery of viral antigens using thousands of rationally designed oligonucleotides. For most viral threats, our ability to respond is hampered by a lack of systematic, high-throughput methods that evaluate and inform the development of therapeutics and vaccines. Although cytotoxic T lymphocytes can afford protection against a wide range of viral antigens, there has not been a systematic investigation of all possible immunogenic peptides. Utilizing a “systems virology” approach, we will design, create, evaluate, and test a large synthetic library of oligos that span large portions of hundreds of human viral pathogens and produce novel candidate targets for vaccine design.

确保世界免受微生物威胁仍然是一项紧迫的挑战，但仍存在巨大差距。 根据我们对病毒性疾病的理解，该提案利用基因组学来满足这三个主要需求： 人类和媒介中新出现的病毒威胁的基因组检测和流行病学对于新出现的病毒， 例如拉沙、埃博拉、寨卡、Powassan 和其他 NIAID A-C 类优先病原体，天然 流行率、进化、遗传多样性以及人类和人畜共患宿主之间的传播 没有得到很好的表征，这威胁到我们准备甚至识别人类病例的能力 病原体基因组学为公共卫生领域的病毒威胁的传播提供了重要的见解。 与西非已建立的临床、公共卫生和学术合作者建立伙伴关系 马萨诸塞州，该项目将对人类患者和人畜共患病宿主的病毒进行测序（非洲 啮齿动物、美洲蜱虫和蚊子），公开分发基因组和宏基因组数据集，并迅速 提供与这些病毒的进化、流行病学和生态学相关的分析，重点是洞察 这可以为正在进行的诊断、治疗和其他干预策略的开发工作提供信息。 病毒出血期间宿主反应和病毒动力学的组织特异性和单细胞特征 病毒性出血性高烧（VHF）如埃博拉病毒和拉沙病毒是致命的，但分子机制如何？ 致命和非致命病例之间细胞宿主反应机制的不同尚不清楚。 与 NIAID 位于马里兰州弗雷德里克的综合研究机构 (BSL-4) 合作，该项目将在 动物模型生物体内 VHF 感染，同时分析宿主转录反应 以及病毒在不同宿主组织内的复制和进化，并利用单细胞 RNA-seq 方法 询问个体宿主 PBMC 类型，这将为细胞特异性宿主反应提供新的认识。 VHF 感染，深入了解死亡和康复背后的不同机制，并告知 制定 VHF 对策。 对于大多数病毒，使用数千种合理设计的寡核苷酸系统地发现病毒抗原。 威胁时，我们的应对能力因缺乏评估和评估的系统性、高通量方法而受到限制。 尽管细胞毒性 T 淋巴细胞可以提供保护，但它为治疗方法和疫苗的开发提供了信息。 针对多种病毒抗原，尚未对所有可能的病毒抗原进行系统研究 利用“系统病毒学”方法，我们将设计、创建、评估和测试一种免疫原性肽。 大型寡核苷酸合成文库，涵盖数百种人类病毒病原体的大部分并产生 疫苗设计的新候选目标。