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: 10163677
• 负责人: Pardis Christine Sabeti
• 金额: $ 68.75万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163677
• 关键词: Address; Africa; African; American; Animal Model; Antigen Presentation; Antigens; Biological Assay; Blood Circulation; Categories; Cells; Cessation of life; Clinical; Communicable Diseases; Culicidae; Cytotoxic T-Lymphocytes; Data; Data Set; Detection; Development; Diagnostic; Disease; Ebola; Ecology; Ensure; Epidemiology; Evolution; Genetic Transcription; Genetic Variation; Genomics; Human; Immune Targeting; Immune response; Immune system; In Vitro; Individual; Infection; Institutes; Intervention; Investigation; Lead; Libraries; Massachusetts; Metagenomics; Methods; Molecular; Movement; National Institute of Allergy and Infectious Disease; Oligonucleotides; Pathology; Patients; Peptides; Peripheral Blood Mononuclear Cell; Policies; Population; Powassan virus; Prevalence; Public Health; Public Health Practice; Recovery; Research Personnel; Resources; Rodent; System; Techniques; Technology; Testing; Therapeutic; Ticks; Time; Tissues; Translating; Translations; Vaccinated; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Hemorrhagic Fevers; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; ZIKA; Zoonoses; combat; design; experience; human disease; immunogenic; immunogenicity; in vivo; innovation; insight; microbial; novel; pathogen; pathogen genomics; pathogenic virus; priority pathogen; research facility; response; ribosome profiling; single-cell RNA sequencing; synthetic biology; therapeutic development; transmission process; vaccine development; vector; viral genomics; virology

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个紧迫的挑战。但是，仍然存在明显的差距 在我们对病毒疾病的理解中。该提案员工基因组学以满足这三个主要需求： 人类和向量中新兴病毒威胁的基因组检测和流行病学。对于新兴病毒， 例如Lassa，Ebola，Zika，Powassan和其他NIAID类别A-C优先病原体，自然 人类和人畜共患宿主之间和人物之间的患病率，进化，遗传多样性以及传播是 表征不佳，这威胁着我们在人类案件中做准备甚至识别的能力 发生。病原体基因组学为病毒威胁的运动提供了关键的公共卫生洞察力。 与西非的临床，公共卫生和学术合作者与既定的临床，公共卫生和学术合作者的合作关系 马萨诸塞州，该项目将序列人类患者和人畜共患病毒（非洲人） 啮齿动物，美国壁虱和蚊子），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，重点是见解 这可能会为诊断，治疗和其他干预策略的持续发展工作提供信息。 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 发烧感染。埃博拉病毒和LASSA等病毒出血狂（VHFS）是高度致命的，但分子如何 致命病例和非致命病例之间不同的细胞宿主反应机制知之甚少。在 与NIAID在马里兰州弗雷德里克（BSL-4）的综合研究机构的合作关系，该项目将在 动物模型生物中的体内VHF感染，只需分析宿主转录反应 以及不同宿主组织内的病毒复制和进化，并使用单细胞RNA-seq方法 询问单个主机PBMC类型。这将为细胞特定宿主的响应提供新的理解 VHF感染，深入了解死亡和康复背后的区别机制，并告知 开发VHFS的对策。 使用数千种理性设计的寡核苷酸对病毒抗原的系统发现。对于大多数病毒 威胁，我们的响应能力受到评估和评估和 尽管细胞毒性T淋巴细胞可以提供保护 在广泛的病毒抗原中，没有对所有可能的系统进行研究 免疫原性肽。利用“系统病毒学”方法，我们将设计，创建，评估和测试 横跨数百种人类病毒病原体并产生大部分的寡寡核心库 疫苗设计的新型候选目标。