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.

许多非传染性疾病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人群之间有所不同 男女。尽管这些影响可以反映性别（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 差异具有生物学成分。结核病（TB），一种细菌感染性疾病，是最常见的疾病之一 全球十大死亡原因，表现出性别二态性。男性结核病比女性更常见、更严重； 人类和小鼠研究证明了流行病学观察到的性别的生物学成分 二态性。目前的提议源于我们令人惊讶的观察，即人类巨噬细胞分化 在没有自体血清的情况下离体单核细胞在结核分枝杆菌感染控制中表现出性别偏见。性别 在脂滴的积累中也观察到了偏差，这是与减少相关的一个特征 受雷帕霉素复合物 1 机制靶标调节的抗分枝杆菌巨噬细胞活性 (mTORC1) 信号传导。目前的提案将确定性激素是否决定对支原体的控制。 通过诱导单核细胞/巨噬细胞表观遗传重编程并涉及 mTORC1 来控制结核感染 发信号。实验计划源于我们的初步结果和实际情况的考虑 文学。首先，在上述中不存在自体血清，因此不存在内源性激素—— 上述实验与观察到的性别偏见中记忆先天反应的参与是一致的。 其次，可预防结核病的记忆先天反应受到表观遗传调控。三、mTORC1 信号传导受到性激素和表观遗传的调节。罗格斯大学的临床能力和专业知识 大学将为代表不同性类固醇激素环境的人群提供机会：(a) 顺性别 服用激素避孕药的女性以及怀孕期间和怀孕后在罗格斯 NJMS 注册的女性 妇产科诊所； (b) 罗格斯跨性别健康中心的跨性别男性和女性。我们有 阐明了该提案的两个目标。我们将利用性类固醇激素血浆水平的变化 外源性给药（目标 1A）和妊娠（目标 1B）以确定激素之间的关系 水平、免疫细胞的表观遗传特征以及结核分枝杆菌感染的控制。在目标 2 中，我们将确定 我们在巨噬细胞控制结核分枝杆菌感染中观察到的性别偏见是否依赖于 mTORC1。 拟议工作的结果将指导针对性、怀孕、 和性类固醇激素治疗。此外，该计划的基本意义和转化意义是 普遍存在于许多其他疾病中的性别偏见。