Role of IFNe in immune modulation and HIV infection

IFNe在免疫调节和HIV感染中的作用

• 批准号: 10356898
• 负责人: Theresa L Chang
• 金额: $ 60.28万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356898
• 关键词: AIDS prevention; Acute; Biological Response Modifiers; Biopsy; Blood; Cells; Cervical; Chronic; Clinical; Data; Disease; E protein; Effector Cell; Elements; Estrogen Therapy; Estrogens; Exhibits; Exposure to; Female; Gene Expression; Gene Expression Regulation; Genes; Goals; HIV; HIV Infections; HIV Seronegativity; HIV resistance; Human; IFNAR1 gene; Immune; Immune response; Immunity; In Vitro; Infection; Interferon-alpha; Interferons; Knowledge; Mediating; Menstrual cycle; Modeling; Molecular; Molecular Cloning; Mucosal Immunity; Mucous Membrane; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytosis; Plasma; Play; Postmenopause; Predisposition; Process; Production; Property; Publishing; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Sampling; Seminal Plasma; Seminal fluid; Sexually Transmitted Diseases; Signal Transduction; Testing; Tissues; Toll-Like Receptor Pathway; Vagina; Variant; Viral; Viral Load result; Viral Physiology; Viral reservoir; Virus; Woman; cervical biopsy; cervicovaginal; chronic infection; clinically relevant; cohort; cytokine; differential expression; humanized mouse; immune activation; immune function; immunoregulation; in vivo; longitudinal analysis; macrophage; mouse model; prevent; receptor; recruit; reproductive tract; resistant strain; sex; transcriptome; transmission process; virus host interaction

Project Summary Interferon e (IFNe) is a critical innate immune mediator that protects the host against sexually transmitted infections. Although the current paradigm is that IFNε is a type I IFN and signals through IFNa receptors, our and other published results show that IFNε has unique immune functions that are distinct from IFNa/b. IFNε is highly abundant in the mucosa of the female reproductive tract, and has superior mucosal immune activity compared to IFNa/b. IFNe gene expression is regulated by estrogen, cytokines, and seminal plasma, but is not induced by Toll-like receptor pathways, which induce IFNa/b. Clinical evidence indicates a protective role of IFNe against HIV. IFNe expression is positively associated with estrogen levels during the menstrual cycle, and inversely correlates with HIV susceptibility. Importantly, HIV-negative sex workers with frequent exposure to semen have an increased level of IFNe gene expression, and have increased numbers of immune effector cells in cervical tissues. We recently demonstrate that IFNe induces an anti-HIV state through a mechanism independent of known type I IFN-induced HIV host restriction factors in primary macrophages. Additionally, IFNε elicits a more robust immune response than IFNa2. We hypothesize is that IFNe displays a dual role in HIV inhibition by protecting HIV target cells and by modulating immune functions, and will test our hypothesis by determining the immune mechanism of IFNe and its impact on HIV infection in vitro, cervical explants and in humanized mouse model. To gain a better understanding of the molecular mechanism of IFNe-mediated HIV inhibition, we determine viral determinants important for IFNe sensitivity. Because estrogen is known to modulate IFNe expression and mucosal immunity, we will assess the impact of estrogen on IFNε-mediated processes in HIV infection in postmenopausal women before and after estrogen treatment. Elucidating the properties and functions of IFNe promises to expand our knowledge of virus-host interactions crucial for HIV prevention and control of viral reservoirs and immunopathogenesis.

项目概要 干扰素 e (IFNe) 是一种重要的先天免疫介质，可保护宿主免受性传播疾病的侵害 尽管目前的范式认为 IFNε 是 I 型 IFN，并通过 IFNα 受体发出信号，但我们的研究表明， 和其他已发表的结果表明，IFNε 具有不同于 IFNa/b 的独特免疫功能。 女性生殖道粘膜中含量丰富，具有优异的粘膜免疫活性 与 IFNa/b 相比，IFNe 基因表达受雌激素、细胞因子和精浆调节，但不受此影响。 由 Toll 样受体途径诱导，诱导 IFNa/b 的临床证据表明具有保护作用。 IFNe 对抗 HIV IFNe 表达与月经周期中的雌激素水平呈正相关，并且 重要的是，经常接触艾滋病毒的性工作者与艾滋病毒易感性呈负相关。 精液中 IFNe 基因表达水平升高，免疫效应子数量增加 我们最近证明，IFNe 通过一种机制诱导抗 HIV 状态。 独立于原代巨噬细胞中已知的 I 型 IFN 诱导的 HIV 宿主限制因素。 IFNε 比 IFNa2 更能引发更强的免疫反应，我们发现 IFNe 具有双重作用。 通过保护 HIV 靶细胞和调节免疫功能来抑制 HIV，并将检验我们的假设 通过确定 IFNe 的免疫机制及其对体外、宫颈外植体和体内 HIV 感染的影响 人源化小鼠模型，以更好地了解 IFNe 介导的 HIV 的分子机制。 抑制，我们确定了对 IFNe 敏感性重要的病毒决定因素，因为已知雌激素会影响 IFNe 的敏感性。 调节 IFNe 表达和粘膜免疫，我们将评估雌激素对 IFNε 介导的影响 绝经后妇女在雌激素治疗前后艾滋病毒感染的过程。 IFNe 的特性和功能有望扩展我们对 HIV 至关重要的病毒与宿主相互作用的了解 预防和控制病毒库和免疫发病机制。

项目成果

ERRγ, a new player in the type I IFN arena.

ERRγ，I型干扰素领域的新玩家。

• 发表时间: 2021-05
• 影响因子: 5.5
• 作者: Xu, Chuan;Chang, Theresa L
• 通讯作者: Chang, Theresa L

Multifaceted immune functions of human defensins and underlying mechanisms.

人类防御素的多方面免疫功能和潜在机制。

• 发表时间: 2019
• 影响因子: 7.3
• 作者: Fruitwala, Saahil;El;Chang, Theresa L
• 通讯作者: Chang, Theresa L

Human Immunodeficiency Viruses Pseudotyped with SARS-CoV-2 Spike Proteins Infect a Broad Spectrum of Human Cell Lines through Multiple Entry Mechanisms.

用 SARS-CoV-2 刺突蛋白假型的人类免疫缺陷病毒通过多种进入机制感染多种人类细胞系。

• 发表时间: 2021
• 作者: Xu, Chuan;Wang, Annie;Geng, Ke;Honnen, William;Wang, Xuening;Bruiners, Natalie;Singh, Sukhwinder;Ferrara, Fortunato;D'Angelo, Sara;Bradbury, Andrew R M;Gennaro, Maria Laura;Liu, Dongfang;Pinter, Abraham;Chang, Theresa L
• 通讯作者: Chang, Theresa L

Differential Effects of Antiseptic Mouth Rinses on SARS-CoV-2 Infectivity In Vitro.

抗菌漱口水对 SARS-CoV-2 体外感染性的不同影响。

• 发表时间: 2021-03-01
• 作者: Xu, Chuan;Wang, Annie;Hoskin, Eileen R;Cugini, Carla;Markowitz, Kenneth;Chang, Theresa L;Fine, Daniel H
• 通讯作者: Fine, Daniel H

Brilacidin, a Non-Peptide Defensin-Mimetic Molecule, Inhibits SARS-CoV-2 Infection by Blocking Viral Entry.

Brilacidin 是一种非肽防御素模拟分子，通过阻止病毒进入来抑制 SARS-CoV-2 感染。

• 发表时间: 2022-04
• 作者: Xu, Chuan;Wang, Annie;Honnen, William;Pinter, Abraham;Weston, Warren K;Harness, Jane A;Narayanan, Aarthi;Chang, Theresa L
• 通讯作者: Chang, Theresa L