Sex hormones and innate immunity in tuberculosis

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不同 男人和女人。尽管这些影响可以反映性别(男性和女性之间的生物差异) 或性别(与男性或女性相关的文化规范)，大量证据支持这些 差异有一个生物学成分。结核病(TB)是一种细菌性传染病，是世界上最大的 全球十种死亡原因，表现出性别二型性。结核病在男性中比女性更常见、更严重； 人类和小鼠的研究证明了流行病学观察到的性别的一个生物学成分 两面性。目前的建议源于我们令人惊讶的观察到人类巨噬细胞分化 在缺乏自体血清的情况下，体外培养的单核细胞在控制结核分枝杆菌感染方面存在性别偏见。性 在脂滴的积累中也观察到了偏见，这是与减少有关的特征 雷帕霉素复合体1机制靶点调控的抗分枝杆菌巨噬细胞活性 (MTORC1)信令。目前的提案将决定性激素是否决定了对M。 单核/巨噬细胞表观遗传重编程及mTORC1参与的结核感染 发信号。该试验计划源于我们的初步结果和 文学。首先，在上述情况下，缺乏自体血清，因此缺乏内源性性激素- 上述实验与记忆先天反应参与观察到的性别偏见是一致的。 第二，防止结核病的记忆先天反应是受表观遗传调控的。第三，mTORC1 信号由性激素调节，也受表观遗传调节。罗格斯大学的临床能力和专业知识 大学将提供接触代表多种性类固醇激素环境的人群的机会：(A)顺性 在罗格斯NJMS接受激素避孕药的妇女和在怀孕期间和怀孕后登记的妇女 妇产科诊所；和(B)罗格斯变性人健康中心的变性人。我们有 将这一提议阐述为两个目的。我们将利用血浆性类固醇激素水平的变化 外源性给药(目标1A)和怀孕(目标1B)以确定激素之间的关系 免疫细胞的水平、表观遗传学特征和结核分枝杆菌感染的控制。在目标2中，我们将确定 我们在结核分枝杆菌感染的巨噬细胞控制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结核病的干预策略，涉及性别、怀孕、 性类固醇激素治疗。此外，该计划的基本含义和翻译含义是 在许多其他疾病中可概括为性别偏见。

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.