Immunogenomics of susceptibility to tuberculosis (TB) among nonhuman primate species

非人灵长类动物结核病易感性的免疫基因组学

• 批准号: 10526201
• 负责人: Morteza Roodgar
• 金额: $ 11.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526201
• 关键词: Address; Advisory Committees; Affect; African Green Monkey; Bacteria; Biological Assay; Blood Cells; Cause of Death; Cells; Cercopithecidae; Cercopithecus tantalus; Communicable Diseases; Data; Disease susceptibility; Drug Targeting; Ectopic Expression; Environment; Enzymes; Exhibits; Family suidae; Gene Proteins; Genes; Genetic Polymorphism; Genome; Genomic approach; Genomics; Goals; Human; Immune; Immune Response Genes; Immune response; Immunity; Immunogenetics; Immunogenomics; Immunologic Markers; Immunology; In Vitro; Infection; Innate Immune Response; Innate Immune System; Interferon Type II; Macaca; Macaca fascicularis; Macaca mulatta; Macaca nemestrina; Measures; Medicine; Mentored Research Scientist Development Award; Mentors; Methods; Modeling; Molecular; Mycobacterium tuberculosis; NOS2A gene; Nitric Oxide; Orthologous Gene; Pathogenesis; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Play; Population; Predisposition; Prevention; Primates; Protein Isoforms; Recording of previous events; Research; Resistance; Respiratory Disease; Rhesus; Risk; Role; System; Tail; Testing; Training; Tuberculosis; Vaccines; Variant; acute infection; comparative; comparative genomics; cytokine; experience; experimental study; genome annotation; human data; insight; lens; macrophage; member; nonhuman primate; novel; novel strategies; response; single-cell RNA sequencing; transcriptome sequencing; transmission process; tuberculosis treatment; whole genome

Tuberculosis (TB) is a respiratory disease that causes the death of 1.5 million people each year. Approximately 30% of the human population worldwide are latently infected with TB, creating a risk for developing active TB and transmission. Genomic studies have attempted to identify innate immune genes and polymorphisms that affect susceptibility to TB among humans. Despite findings that suggest correlation of certain genetic polymorphisms in specific immune genes with TB susceptibility, genomic studies have failed to identify specific isoforms that might influence human TB susceptibility. This is because innate immune genes are highly conserved among humans, making them exhibit similar immune responses to TB bacteria. By contrast, different species of nonhuman primates exhibit different levels of susceptibility to TB. Rhesus macaques (macaca mulatta) are more susceptible to TB compared to cynomolgus macaques (macaca fascicularis), yet the underlying mechanism of this variation is unknown. It is crucial to compare innate immune response genes across primate species in response to TB infection to identify the differences in immune orthologs that help eliminate TB bacteria. Using comparative genomics approaches, this study explores and characterizes immune responses across species by ex-vivo infection of different primate blood cells with TB bacteria using long-read RNA-Seq. The use of long-read RNA-Seq provides a more comprehensive annotation of innate immune orthologs across primate species which wasn’t possible in past studies using short-read RNA-seq. This study will help identify species-specific immune orthologs important in immunity against TB, which might ultimately be used to evaluate drug targets for human TB prevention and treatment. This comparative genomic approach can also be applied to identify species-specific immune orthologs as drug targets for other infectious diseases.

结核病（TB）是一种呼吸道疾病，每年导致150万人死亡。大约 全世界30％的人口被结核病感染，造成了发展活跃结核病的风险 和传输。基因组研究试图识别先天免疫基因和多态性 影响人类对结核病的敏感性。尽管发现表明某些遗传的相关性 具有结核病敏感性的特定免疫原的多态性，基因组研究未能鉴定特定 可能影响人类结核病敏感性的同工型。这是因为先天免疫基因高度高 在人类中保守，使它们暴露于与结核病细菌相似的免疫复杂。相比之下，不同 非人类素质物种表现出不同水平的TB敏感性。恒河猕猴（澳门） 与cynomolgus猕猴（Macaca fascicularis）相比，Mulatta更容易受到结核病的影响，但是 这种变异的基本机制尚不清楚。比较先天免疫响应基因至关重要 跨越主要物种响应结核病感染，以确定有助于的免疫直系同源物的差异 消除结核病细菌。使用比较基因组学方法，本研究探索和特征免疫 通过长阅读，通过TB细菌对不同原代血细胞的外感染对跨物种的反应 RNA-seq。长阅读RNA-seq的使用提供了对先天免疫的更全面的注释 在过去的研究中，使用短读RNA-Seq在过去的研究中不可能的直系同源物。这项研究会 帮助确定针对TB免疫力重要的特定规范免疫直系同源物，最终可能是 用于评估人类结核病预防和治疗的药物靶标。这种比较基因组方法可以 还可以应用于识别规格特异性免疫学作为其他传染病的药物靶标。