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 全球 30% 的人口潜伏感染结核病，存在发展为活动性结核病的风险 和传输。基因组研究试图鉴定先天免疫基因和多态性 影响人类对结核病的易感性。尽管研究结果表明某些遗传因素之间存在相关性 特定免疫基因的多态性与结核病易感性有关，但基因组研究未能确定特定免疫基因的多态性 可能影响人类结核病易感性的亚型。这是因为先天免疫基因高度 在人类中保守，使他们对结核菌表现出类似的免疫反应。相比之下，不同 不同种类的非人类灵长类动物对结核病表现出不同程度的易感性。恒河猴（猕猴 与食蟹猴（猕猴）相比，穆拉塔（Mulatta）更容易感染结核病，但 这种变异的根本机制尚不清楚。比较先天免疫反应基因至关重要 跨灵长类动物物种对结核病感染的反应，以确定免疫直系同源物的差异，从而帮助 消灭结核菌。本研究利用比较基因组学方法，探索并表征了免疫 使用长读长读法通过用结核菌体外感染不同灵长类动物血细胞来进行跨物种反应 RNA测序。长读长RNA-Seq的使用为先天免疫提供了更全面的注释 跨灵长类物种的直系同源物，这在过去使用短读长 RNA-seq 的研究中是不可能的。这项研究将 帮助识别对结核病免疫很重要的物种特异性免疫直系同源物，这最终可能是 用于评估人类结核病预防和治疗的药物靶点。这种比较基因组方法可以 也可用于识别物种特异性免疫直系同源物作为其他传染病的药物靶标。