Characterizing the impact of Yersinia Pestis to the phenotypic evolution of the human immune system

表征鼠疫耶尔森菌对人类免疫系统表型进化的影响

• 批准号: 10631544
• 负责人: Luis Bruno Barreiro
• 金额: $ 31.07万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631544
• 关键词: Address; Administrative Supplement; Africa; African American population; American; Antigens; Applications Grants; Autoimmune Diseases; Biological Assay; Bubonic Plague; CD8-Positive T-Lymphocytes; Cells; Central Africa; Chronic; Collection; Communicable Diseases; Complex; DNA; Data; Development; Disease; Environment; European; Evolution; Exposure to; Funding; Gene Frequency; Genes; Genetic; Genetic Transcription; Genetic Variation; Genetic study; Genotype; Histocompatibility Antigens Class I; Host Defense; Human; Human Genetics; Human Genome; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Individual; Infection; Infectious Agent; Inflammatory; Maps; Mass Spectrum Analysis; Measures; Mediating; Modernization; Molecular; Northern Africa; Parents; Pathogenicity; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Plague; Play; Population; Population Group; Predisposition; Quantitative Trait Loci; Recording of previous events; Resistance; Role; Sampling; Shapes; Time; Variant; Work; Yersinia; Yersinia pestis; cell type; functional genomics; genetic information; genetic variant; genomic locus; human genomics; in vitro Assay; induced pluripotent stem cell; infancy; inter-individual variation; macrophage; pandemic disease; parent grant; pathogen; pressure; protective allele; response; single-cell RNA sequencing; skeletal; tool; trait

Project Summary Pathogens are one of the strongest selective pressures on the human genome. As modern humans migrated out of Africa, they encountered markedly different pathogenic environments, likely resulting in population-specific selection of immune phenotypes. Consistent with this hypothesis, some of the most compelling evidence for local positive selection in the human genome has been detected among genes involved in immunity and host defense. Yet, our understanding of the role that local adaptation plays in shaping phenotypic variation in immune responses across populations is still in its infancy. To better understand the complex relationship between pathogens and host adaptation we propose to study the selective impact on the immune system of one of the most devastating pathogens in history – Yersinia pestis, the agent of the Black Death. Since its emergence in Eurasia 1500 to 6400 years ago Y. pestis has swept Eurasia and North and Central Africa in two major pandemics (Justinian, 541-544; Black Death, starting 1347-1351) and has subsequently spread nearly worldwide via a third ongoing pandemic. Although Y. pestis is proposed to have severely culled the Eurasian population, how groups that differ in their historical exposure to plague respond to the pathogen is not known. 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 diseases, chronic inflammatory disorders, and autoimmune disorders. Using combined expertise in human genomics, immunology, infectious diseases and ancient DNA, the parent R01 proposes: (i) to characterize inter-individual and inter- population variability in immune responses to infection with Y. pestis in human macrophages; (ii) to map expression quantitative trait loci (eQTLs) that are associated with variation in response to infection with Y. pestis; and (iii) to identify genetic loci showing signatures of positive selection by Y. pestis by looking at “real-time” fluctuations in allele frequencies among immune-related genes and immunological QTLs sequenced from skeletal remains of European populations living before, during, and after the Black Death. As part of this supplement, we propose (i) to expand the scope of the work to investigate the impact of genetic variation in immune responses to Y. pestis across a larger array of immune cell types by leveraging the recent development of single cell RNAseq approaches, and (ii) to investigate the impact of ERAP2 variants that were positively selected during the Black Death to the repertoire of Y. pestis MHC-associated peptides (MAPs) and, ultimately, host protection against Y. pestis.

项目摘要 病原体是人类基因组上最强的选择压力之一。随着现代人类的迁移 在非洲之外，他们遇到了明显不同的致病环境，可能导致人口特异性 免疫表型的选择。与这一假设一致，这是一些最令人信服的证据 在与免疫和宿主有关的基因中发现了人类基因组中的局部阳性选择 防御。然而，我们对局部适应在塑造免疫中表型变异中所起的作用的理解 人口之间的反应仍处于起步阶段。更好地了解 病原体和宿主适应我们建议研究对其中一种的免疫系统的选择性影响 历史上最毁灭性的病原体 - 黑死的耶西尼亚·佩斯蒂斯（Yersinia Pestis）。自从它出现以来 欧亚大陆1500至6400年前Y. Pestis在两个主要的 大流行（Justinian，541-544;黑死亡，从1347-1351开始），随后几乎在全球范围内传播 通过第三次正在进行的大流行。尽管建议佩斯蒂斯（Y. Pestis）严重淘汰了欧亚人口，但 尚不清楚其历史暴露对鼠疫的历史暴露的群体如何应对病原体。寻址 这个差距不仅对于理解人类免疫系统的最新演变很重要，而且也可能 帮助揭示与祖先相关的传染病易感性差异的分子基础 炎症性疾病和自身免疫性疾病。使用人类基因组学，免疫学，合并专业知识， 传染病和古代DNA，父母R01提案：（i）表征个体间和间 人类巨噬细胞中对感染的免疫反应的人群变异性； （ii）映射 表达定量性状位置（EQTL）与鼠疫感染有关的变异相关； （iii）通过查看“实时”来确定Y. Pestis阳性选择的遗传定位特征 免疫相关基因和免疫QTL中等位基因频率的波动从 欧洲人口的骨骼遗体居住于黑人死亡之前，期间和之后。作为其中的一部分 补充，我们建议（i）扩大工作范围，以研究遗传变异对 通过利用近期发展，对Y. pestis的免疫反应在更大的免疫细胞类型中产生 单细胞RNASEQ方法和（ii）研究ERAP2变体的影响 在黑人死亡期间被选为佩斯蒂斯MHC相关的Pepperides（地图）的曲目，并最终 对Y. PESTIS的宿主保护。

项目成果

[The Black Death, natural selection and susceptibility to auto-immune disorders].

[黑死病、自然选择和对自身免疫性疾病的易感性]。

• DOI: 10.1051/medsci/2023050
• 发表时间: 2023
• 期刊: Medecine sciences : M/S
• 作者: Demeure,ChristianE;Poinar,Hendrik;Barreiro,Luis;Pizarro-Cerdá,Javier
• 通讯作者: Pizarro-Cerdá,Javier