Sex hormones and innate immunity in tuberculosis

结核病中的性激素和先天免疫

• 批准号: 10186699
• 负责人: Maria Laura Gennaro
• 金额: $ 19.61万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186699
• 关键词: Adult; Antimycobacterial Agents; Appearance; Autologous; Biological; Blood specimen; Cause of Death; Cells; Chromatin; Clinic; Clinical; Communicable Diseases; Complex; Disease; Disease susceptibility; Enrollment; Epidemiology; Epigenetic Process; Exhibits; FRAP1 gene; Female; Gender; Gonadal Steroid Hormones; Growth; Health; Hormonal; Hormones; Human; Immune; Immunologic Memory; Incidence; Infection; Infection Control; Intervention; Link; Lipids; Literature; Memory; Metabolism; Mus; Mycobacterium tuberculosis; Natural Immunity; Outcome; Pathogenesis; Pathway interactions; Plasma; Population; Postpartum Period; Predisposition; Pregnancy; Pregnant Women; Protein Kinase; Puberty; Reporting; Sampling; Serum; Severities; Sex Bias; Sex Differences; Sexual Maturation; Signal Transduction; Solid; Specialist; Stimulus; Testing; Time; Tuberculosis; Universities; Vaccination; Variant; Woman; Work; antimicrobial; cis-female; cis-male; epidemiology study; experimental study; genome-wide; genotypic sex; hormonal contraception; hormone therapy; immune function; improved; in vivo; inhibitor/antagonist; macrophage; male; men; monocyte; mortality; mycobacterial; peripheral blood; recruit; response; sex; sexual dimorphism; stem; transgender; transgender men; transgender women; tuberculosis immunity

Incidence and severity of many non-infectious and infectious diseases and vaccination efficacy differ between men and women. Although these effects could reflect sex (the biological differences between male and female) or gender (cultural norms associated with being male or female), a large body of evidence supports that these differences have a biological component. Tuberculosis (TB), a bacterial infectious disease that is one of the top ten causes of death worldwide, exhibits sex dimorphism. TB is more frequent and severe in men than women; human and murine studies demonstrate a biological component of the epidemiologically observed sex dimorphism. The present proposal stems from our surprising observation that human macrophages differentiated from monocytes ex vivo in absence of autologous serum exhibit sex bias in M. tuberculosis infection control. Sex bias was also observed in the accumulation of lipid droplets, a feature associated with decreased antimycobacterial macrophage activity that is regulated by mechanistic target of rapamycin complex 1 (mTORC1) signaling. The present proposal will determine whether sex hormones determine control of M. tuberculosis infection by inducing epigenetic reprogramming in monocytes/macrophages and involving mTORC1 signaling. The experimental plan stems from considerations derived from our preliminary results and the literature. First, the absence of autologus serum, and therefore endogenous sex hormones, in the above- mentioned experiments is consistent with the involvement of memory innate responses in the observed sex bias. Second, memory innate responses, which protect against TB, are epigenetically regulated. Third, mTORC1 signaling is regulated by sex hormones and also epigenetically. The clinical capacity and expertise at Rutgers University will provide access to populations that represent a diverse sex steroid hormone milieu: (a) cis-gender women taking hormonal contraceptives and women enrolled during and after pregnancy at the Rutgers NJMS OB/GYN clinic; and (b) transgender men and women at the Rutgers Center for Transgender Health. We have articulated this proposal in two aims. We will leverage variations of plasma levels of sex steroid hormones due to exogenous administration (Aim 1A) and pregnancy (Aim 1B) to determine relationships between hormonal levels, epigenetic profiles in immune cells, and control of M. tuberculosis infection. In Aim 2, we will determine whether the sex bias we observe in the macrophage control of M. tuberculosis infection is mTORC1-dependent. The results of the proposed work will guide interventional strategies against TB with respect to sex, pregnancy, and sex steroid hormonal therapy. Moreover, the fundamental and translational implications of the plan are generalizable to sex bias in many other diseases.

许多非传染性和传染性疾病的发病率和严重程度以及疫苗接种效果在不同国家之间存在差异。 男人和女人尽管这些影响可能反映了性别（男性和女性之间的生物学差异） 或性别（与男性或女性相关的文化规范），大量证据支持这些 差异有生物学的成分。结核病（TB）是一种细菌性传染病， 全球十大死因之一，显示出性别二态性。结核病在男性中比在女性中更为常见和严重; 人类和鼠类研究表明，流行病学观察到的性别存在生物学成分， 二型性目前的建议源于我们惊人的观察，人类巨噬细胞分化 在不存在自体血清的情况下，来自离体单核细胞的单核细胞在M中表现出性别偏倚。结核病感染控制性 在脂滴积累中也观察到偏倚，这是一个与降低 由雷帕霉素复合物1的机制靶点调节的抗分枝杆菌巨噬细胞活性 （mTORC 1）信号传导。目前的建议将确定是否性激素决定控制M。 通过诱导单核细胞/巨噬细胞中的表观遗传重编程并涉及mTORC 1的结核感染 发信号。实验计划源于对我们的初步结果的考虑， 文学首先，在上述病例中，缺乏自体血清，因此缺乏内源性激素- 上述实验与所观察到的性别偏见中的记忆先天反应的参与是一致的。 第二，防止结核病的记忆先天反应是表观遗传调节的。mTORC1 信号传导受性激素和表观遗传学的调节。罗格斯大学的临床能力和专业知识 大学将提供访问人口，代表了一个多样化的性类固醇激素环境：（a）顺性别 服用激素避孕药的妇女和在Rutgers NJMS怀孕期间和怀孕后登记的妇女 OB/GYN诊所;和（B）罗格斯变性人健康中心的变性人男性和女性。我们有 这一建议有两个目的。我们将利用性类固醇激素的血浆水平的变化， 外源性给药（目的1A）和妊娠（目的1B），以确定激素之间的关系 水平，免疫细胞中的表观遗传特征，以及M.肺结核感染。在目标2中，我们将确定 我们在M.结核感染是mTORC 1依赖性的。 拟议工作的结果将指导在性别、怀孕、 和性类固醇激素治疗此外，该计划的基本和转化影响是 可推广到许多其他疾病中的性别偏见。