Characterizing variation and adaptation in the immune response to plague (Y. pestis) through single-cell sequencing and ancient genomics

通过单细胞测序和古代基因组学表征鼠疫（鼠疫耶尔森氏菌）免疫反应的变异和适应

• 批准号: 10332521
• 负责人: Tauras P Vilgalys
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332521
• 关键词: Address; Affect; Africa; Africa South of the Sahara; African; African ancestry; Area; Autoimmune; Autoimmune Diseases; Automobile Driving; Bacteria; Basic Science; Blood Cells; Bubonic Plague; Cell Culture Techniques; Cells; Chronic; Communicable Diseases; DNA; Data; Disease; Disease susceptibility; Environment; Europe; European; Event; Evolution; Exposure to; Frequencies; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Grain; Health; Host Defense; Human; Human Genome; Immune; Immune response; Immune system; Immunity; Immunologics; Individual; Infection; Inflammation; Inflammatory; Influentials; Invaded; Link; Mediating; Mentors; Modernization; Molecular; Natural Selections; Pasteurella pseudotuberculosis; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Plague; Population; Population Genetics; Positioning Attribute; Predisposition; Quantitative Trait Loci; Recording of previous events; Research Design; Resistance; Sampling; Shapes; Testing; Time; Training; Variant; Work; Yersinia; Yersinia pestis; cell type; disorder risk; emerging pathogen; experience; functional genomics; genetic approach; genetic variant; genome sequencing; genomic data; genomic locus; genomic signature; health disparity; host-pathogen coevolution; human pathogen; immune function; in vitro Assay; in vivo; insight; interest; macrophage; mortality; novel; pathogen; pressure; protective allele; response; single cell sequencing; single-cell RNA sequencing

PROJECT SUMMARY Pathogens have been one of the strongest selective pressures in human evolution. Migrating out of Africa, modern humans encountered novel pathogens along with new environments. These populations likely adapted to these pathogens, leading to population-specific adaptations. Consistent with this hypothesis, some of the most compelling signatures of local adaptation in the human genome overlap genes involved in immunity and host defense. Importantly, these regions also overlap genetic loci which are associated with infectious, autoimmune, and inflammatory disease risk in modern humans. Thus, understanding adaptation to pathogens throughout history is important for understanding modern human health. The Black Plague was likely one of the strongest selective events in recent human history. Exposure to Yersinia pestis (the causative agent of plague) therefore likely drove adaptations in the human immune system which continue to shape modern immune variation. Importantly, because the plague ravaged Eurasia while leaving sub-Saharan Africa relatively untouched, adaptation to plague likely occurred in European but not African populations. However, it is not known whether human populations differ in their immune response to plague as a consequence of prior evolutionary history. Addressing this gap is not only important for understanding the recent evolution of the human immune system, but may also help reveal the molecular basis of ancestry-related differences in susceptibility to infectious disease, chronic inflammation, and autoimmune disorders. The basic research questions driving this proposal are: What was the impact of Y. pestis to the functional differentiation of immune responses between African- and European-ancestry individuals? To which extent natural selection has favored the increase in frequency of protective alleles in Europeans, a population with increased exposure to Y. pestis? What cell types and immunological pathways show the most divergence in response to Y. pestis between populations? To answer this questions, I will experimentally infected peripheral blood cells in culture to characterize the immune response to plague. Using single-cell RNA sequencing I will be able to analyze variation in the immune response across cell types, but also characterize differences in the proportion of cells responding to infection and the strength of that response. Using this data, I will identify genes and pathways which are regulated differently in individuals of European and African ancestry, and identify genetic variants which contribute to these differences. I will then use a combination of ancient and modern genomics to test whether loci underlying variation in the immune response to Y. pestis also experienced position selection during the Black Plague. Thus, this project is a novel integration of functional and population genetic approaches to study adaptation to a deadly human pathogen. At its conclusion, this study will reveal how Europeans adapted to Y. pestis exposure during the plague, and identify highly-promising genetic candidates which may contribute to disease susceptibility in modern human populations.

项目概要 病原体一直是人类进化中最强的选择压力之一。迁出非洲， 现代人类遇到了新的病原体和新的环境。这些人群可能已经适应了 这些病原体，导致特定人群的适应。与这一假设相一致的是，一些最 人类基因组中局部适应的引人注目的特征与涉及免疫和宿主的基因重叠 防御。重要的是，这些区域也重叠与传染性、自身免疫性、 和现代人类炎症性疾病的风险。因此，了解对病原体的适应 历史对于理解现代人类健康很重要。 黑死病可能是近代人类历史上最强烈的选择性事件之一。接触 因此，鼠疫耶尔森氏菌（鼠疫病原体）可能推动了人类免疫系统的适应 继续塑造现代免疫变异。重要的是，因为瘟疫肆虐欧亚大陆 撒哈拉以南非洲相对未受影响，对鼠疫的适应可能发生在欧洲而不是非洲 人口。然而，目前尚不清楚人群对鼠疫的免疫反应是否存在差异 先前进化历史的结果。解决这一差距不仅对于理解 人类免疫系统的最新进化，但也可能有助于揭示与祖先相关的分子基础 对传染病、慢性炎症和自身免疫性疾病的易感性存在差异。 推动该提案的基本研究问题是：鼠疫耶尔森氏菌对功能性有何影响？ 非洲和欧洲血统个体之间免疫反应的差异？到什么程度 自然选择有利于欧洲人保护性等位基因频率的增加，这个群体具有 增加接触鼠疫耶尔森氏菌？哪些细胞类型和免疫途径表现出最大的差异 人群之间对鼠疫耶尔森氏菌的反应？为了回答这个问题，我将实验性地感染外设 培养物中的血细胞可表征对鼠疫的免疫反应。使用单细胞 RNA 测序我将 能够分析不同细胞类型的免疫反应的变化，还能够表征不同细胞类型之间的差异 对感染做出反应的细胞比例以及反应的强度。使用这些数据，我将识别基因 以及在欧洲和非洲血统的个体中受到不同调节的途径，以及 识别导致这些差异的遗传变异。然后我将结合使用古代和 现代基因组学测试鼠疫耶尔森氏菌免疫反应中潜在变异的位点是否也经历过 黑死病期间的职位选择。因此，该项目是功能与人口的新颖整合 研究对致命人类病原体的适应的遗传方法。最后，这项研究将揭示如何 欧洲人在鼠疫期间适应了鼠疫耶尔森氏菌的暴露，并发现了极具前景的候选基因 这可能会增加现代人群的疾病易感性。