Genetic and hormonal mechanisms mediating sex differences in TB and TB-HIV

介导结核病和结核病艾滋病毒性别差异的遗传和激素机制

基本信息

批准号：
10484064
负责人：
WILLIAM Ramses BISHAI
金额：
$ 81.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10484064
关键词：
Abbreviations Adoptive Transfer Adrenal Glands Androgens Animal Model Animals Antitubercular Agents Basic Science Biological Biological Factors Bone Marrow Cells Country Disasters Dose Epidemic Epidemiology Epigenetic Process Equilibrium Estrogens Eunuchism Evaluation FOXP3 gene Female Four Core Genotypes Genes Genetic Genotype Gonadal Hormones Gonadal Steroid Hormones Gonadal structure Growth HIV HIV Infections HIV/TB Health Services Accessibility Hormonal Hormones Hour Human Immune Immune response Immunity Immunologics Infection Interferon Type II Interleukin-4 Knockout Mice Lead Leukocytes Link Macrophage Activation Mediating Methods Modeling Molecular Molecular Analysis Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Necrotic Lesion Outcome Pathogenesis Patients Peripheral Blood Mononuclear Cell Persons Pharmacology Play Ploidies Process Processed Genes Research Personnel Resistance Risk Role Sampling Sampling Studies Selective Estrogen Receptor Modulators Severities Sex Bias Sex Chromosomes Sex Differences Signal Transduction T cell response T-Lymphocyte TLR7 gene TLR8 gene TNF gene TNFSF5 gene Testosterone Tuberculosis Whole Blood X Chromosome X Inactivation cytokine dehydroepiandrosterone design epigenetic silencing genetic analysis human female human male immune function macrophage male mouse model multidisciplinary neglect novel response sex tool transcriptomics tuberculosis treatment

项目摘要

PROJECT SUMMARY Tuberculosis (TB) occurs more frequently in males (~70% of cases) than females. While reduced access to care for females and undercounting of female cases may contribute modestly to this longstanding epidemiologic observation in some countries, both human studies (the Lűbeck disaster and eunuch studies) as well as animal models underscore the fact that biological factors play a dominant role in female resistance to TB. Despite the importance of this sex-bias in TB, it has gone largely neglected by basic science researchers. The central scientific premise of this application is that defining the biological mechanisms of the male bias for TB will enlighten our mechanistic understanding of TB pathogenesis and protective human immune responses in TB. A multidisciplinary team with decades of expertise on sex differences (Klein), TB pathogenesis (Bishai), and sex differences in HIV (Scully) will conduct the project. This proposal will investigate the impact of genetics (X chromosome complement) and sex steroid hormones on TB pathogenesis using cellular tools, animal models, and human samples. A key tool used in Aim 1 will be the novel four core genotype (FCG) mouse model, in which animals with XX genotypes have male gonads/hormone levels and those with XY genotypes have female gonads/hormone levels. This model will enable us to differentiate the impact of genetics from those of the sex steroids on murine control of TB. The X chromosome encodes numerous genes of immunologic importance including the genes that encode for TLR7, TLR8, CYBB, NEMO, CD40L, and FOXP3. The process of X-chromosome inactivation (XCI)--in which one female X chromosome is epigenetically silenced--is designed to provide balanced gene dosing between females and males. Certain genes, however, can escape XCI, leading to a double gene dose in females. The process of gene escape from XCI has not been studied in the context of TB, and advanced molecular tools will be used in Aim 2 to investigate gene escape from XCI as a cause of the male bias in severity of TB. While it is widely known that sex steroid signaling modulates immune function, the impact of sex steroids as a basis for the male bias in TB has not been thoroughly investigated. Testosterone has an immunotolerizing effect, reducing levels of IFN-γ and elevating levels of IL-4. In contrast, estrogen promotes higher levels of macrophage activation and increases in TNF-α levels. In Aim 2, we will carefully dissect the role of sex steroids using adoptive transfer methods as well as gonadectomized mice with selective hormone replacement. Lastly, in Aim 3 we will extend these studies to assess the intersection of HIV infection, a critical risk for TB, and sex differences in immunity. We will assess immune responses in samples from people living with HIV (PLWH) on ART versus healthy controls (HCs), specifically balancing groups for sex. We will evaluate the ability of whole blood and hMDM from PLWH and HCs to contain Mtb growth both alone and in the presence of DHEA. Lastly, we will assess transcriptomic responses in PBMCs from male and female PLWH and HCs following Mtb infection.

项目摘要与女性相比，在男性（约70％的病例）中，结核病（TB）的发生频率更高。同时减少获得护理的机会对于女性和女性案件的降低可能对这种长期流行病学造成适度的贡献在某些国家 /地区观察人类研究（LűBeck灾难和太监研究）和动物模型强调了生物因子在女性对结核病的耐药性中起主要作用的事实。尽管有这种性别偏见在结核病中的重要性，它在很大程度上被基础科学研究人员所忽略了。中央该应用的科学前提是，定义男性偏见的生物学机制将启发了我们对结核病发病机理的机械理解，并保护了结核病中的人类免疫回报。一个多学科团队具有数十年的性别差异专业知识（Klein），结核病发病机理（Bishai）和性别艾滋病毒（Scully）的差异将进行该项目。该建议将研究遗传学（X染色体完成）和性类固醇激素的影响使用细胞工具，动物模型和人类样品进行结核病发病机理。 AIM 1中使用的关键工具将是新型的四种核心基因型（FCG）小鼠模型，其中具有XX基因型的动物具有雄性性腺/激素水平和具有XY基因型的激素水平具有雌性性腺/激素水平。这个模型将使我们能够区分遗传学与性别立体的影响对TB的鼠控制。 X染色体编码许多免疫学重要性基因，包括编码的基因 TLR7，TLR8，CYBB，NEMO，CD40L和FOXP3。 X染色体灭活的过程（XCI） - 其中一个雌性X染色体是表观遗传沉默的 - 旨在提供平衡的基因剂量女性和男性。但是，某些基因可以逃脱XCI，导致女性的双基因剂量。这从XCI逃脱的基因过程尚未在结核病的背景下进行研究，高级分子工具将在AIM 2中使用，以研究从XCI逃脱的基因，是TB严重程度的男性偏见的原因。众所周知，性类固醇信号传导调节免疫功能，但性类固醇作为一种尚未对结核病中男性偏见的基础进行彻底研究。睾丸激素具有免疫溶液效应，降低IFN-γ水平和IL-4的升高水平。相反，雌激素促进巨噬细胞的较高水平 TNF-α水平的激活和增加。在AIM 2中，我们将使用自适应仔细地剖析性别立体的作用通过选择性激素替代品的转移方法以及性腺切除小鼠。最后，在AIM 3中，我们将扩展这些研究，以评估HIV感染的交集，结核病的关键风险和免疫学上的性别差异。我们将评估来自HIV患者（PLWH）的样本中的免疫反应在艺术与健康对照（HCS）上，特别是平衡性别的群体。我们将评估整体的能力来自PLWH和HCS的血液和HMDM单独和存在DHEA的血液和HMDM。最后，我们将评估MTB感染后男性和女性PLWH和HCS的PBMC中的转录组反应。