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: 10662524
• 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/10662524
• 关键词: Address; Advisory Committees; Affect; African Green Monkey; Bacteria; Biological Assay; Blood Cells; Cause of Death; Cells; Cercopithecidae; Communicable Diseases; Data; Disease susceptibility; Drug Targeting; Ectopic Expression; Environment; Enzymes; Exhibits; Genes; Genetic Polymorphism; Genome; Genomic approach; Genomics; Goals; Human; Immune; Immune Response Genes; Immune response; Immunity; Immunogenetics; Immunogenomics; Immunologic Markers; Immunology; In Vitro; Infection; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type II; Macaca; Macaca fascicularis; Macaca mulatta; Macaca nemestrina; Macrophage; 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; Population; Predisposition; Prevention; Primates; Protein Isoforms; Proteins; Recording of previous events; Research; Resistance; Respiratory Disease; Risk; Role; System; Testing; Training; Tuberculosis; Vaccines; Variant; acute infection; candidate identification; comparative; comparative genomics; cytokine; experience; experimental study; genome annotation; human data; insight; lens; member; nonhuman primate; novel; novel strategies; response; single-cell RNA sequencing; transcriptome sequencing; transmission process; tuberculosis treatment; vervet; 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.

结核病是一种呼吸道疾病，每年造成150万人死亡。约 全世界30%的人口潜伏感染结核病，造成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 在结核病易感性的特定免疫基因中，基因组研究未能确定特定的 可能影响人类结核病易感性的同种型。这是因为先天免疫基因高度 这在人类中是保守的，使他们对结核病细菌表现出类似的免疫反应。相比之下， 不同种类的非人灵长类动物对TB表现出不同程度的易感性。恒河猴（猕猴 与食蟹猴（macacafascicularis）相比， 这种变化的潜在机制是未知的。比较先天免疫反应基因至关重要 在灵长类动物物种中对结核病感染的反应，以确定免疫直系同源物的差异， 消灭结核菌。利用比较基因组学方法，本研究探讨和表征免疫 通过使用长读法对不同灵长类动物血细胞进行TB细菌离体感染的跨物种反应 RNA测序使用长读段RNA-Seq提供了先天免疫的更全面的注释， 灵长类物种之间的直系同源物，这在过去的研究中是不可能使用短读RNA-seq的。本研究将 有助于识别在抗结核免疫中重要的物种特异性免疫直向同源物， 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 也可用于鉴定作为其他传染病药物靶标的物种特异性免疫直系同源物。