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.

项目概要 病原体是对人类基因组最强的选择压力之一。随着现代人类的迁徙 在非洲之外，他们遇到了明显不同的致病环境，可能导致人群特异性 免疫表型的选择。与这一假设相一致的是，一些最令人信服的证据 在人类基因组中与免疫和宿主有关的基因中发现了局部正选择 防御。然而，我们对局部适应在塑造免疫表型变异中所起的作用的理解 跨人群的反应仍处于起步阶段。为了更好地理解之间的复杂关系 病原体和宿主适应我们建议研究其中一种对免疫系统的选择性影响 历史上最具破坏性的病原体——鼠疫耶尔森氏菌，黑死病的病原体。自从它出现以来 1500至6400年前的欧亚大陆鼠疫耶尔森氏菌曾两次席卷欧亚大陆以及北非和中非 流行病（查士丁尼，541-544 年；黑死病，始于 1347-1351 年），随后几乎蔓延到全世界 通过第三次持续的大流行。尽管鼠疫耶尔森氏菌被认为严重消灭了欧亚种群， 不同历史接触鼠疫的群体对病原体的反应尚不清楚。寻址 这一差距不仅对于了解人类免疫系统的近期进化很重要，而且还可能 有助于揭示对传染病、慢性病的易感性方面与祖先相关的差异的分子基础 炎症性疾病和自身免疫性疾病。利用人类基因组学、免疫学方面的综合专业知识， 传染病和古代 DNA，母体 R01 提出：（i）描述个体间和个体间的特征 人类巨噬细胞对鼠疫耶尔森氏菌感染的免疫反应存在群体变异性； (二) 绘制地图 与鼠疫耶尔森氏菌感染反应变异相关的表达数量性状位点 (eQTL)； (iii) 通过“实时”观察来识别显示鼠疫耶尔森氏菌正选择特征的基因位点 免疫相关基因和免疫 QTL 之间等位基因频率的波动 生活在黑死病之前、期间和之后的欧洲人口的骨骼遗骸。作为本次活动的一部分 作为补充，我们建议（i）扩大工作范围以调查遗传变异的影响 利用最新的进展，对多种免疫细胞类型对鼠疫耶尔森氏菌产生免疫反应 单细胞 RNAseq 方法的研究，以及 (ii) 研究 ERAP2 变体的影响，这些变体对 在黑死病期间被选入鼠疫耶尔森氏菌 MHC 相关肽 (MAP) 库，并最终， 针对鼠疫耶尔森氏菌的宿主保护。

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