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.

项目摘要 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。 感染.尽管目前的范例是IFNε是I型IFN并且通过IFN α受体发出信号，但我们的研究发现， 和其他已发表的结果表明，IFNε具有不同于IFN α/B的独特免疫功能。IFNε是 在雌性生殖道粘膜中高度丰富，并具有上级粘膜免疫活性 与IFNa/B相比。IFNe基因表达受雌激素、细胞因子和精浆的调节，但不受雌激素、细胞因子和精浆的调节。 由Toll样受体途径诱导，其诱导IFN α/B。临床证据表明， IFNe抗艾滋病毒。IFNe表达与月经周期中的雌激素水平呈正相关， 与HIV易感性呈负相关。重要的是，艾滋病毒阴性的性工作者经常接触 精液中IFNe基因表达水平增加，免疫效应子数量增加 宫颈组织中的细胞。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宿主限制因子。此外，本发明的目的是， IFNε比IFN α 2产生更强的免疫应答。我们假设IFNe在以下方面显示出双重作用： 通过保护HIV靶细胞和调节免疫功能来抑制HIV，并将验证我们的假设 通过确定IFNe的免疫机制及其对体外HIV感染的影响， 人源化小鼠模型。为了更好地了解IFN介导的HIV的分子机制， 抑制，我们确定了IFNe敏感性重要的病毒决定因素。因为众所周知雌激素 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 绝经后妇女雌激素治疗前后的HIV感染过程。阐明 IFNe的性质和功能有望扩大我们对HIV病毒-宿主相互作用的认识 预防和控制病毒储库和免疫发病机制。

项目成果

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

• DOI: 10.3390/pathogens10030272
• 发表时间: 2021-03-01
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Xu C;Wang A;Hoskin ER;Cugini C;Markowitz K;Chang TL;Fine DH
• 通讯作者: Fine DH

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
• 期刊: EC microbiology
• 作者: Xu,Chuan;Wang,Annie;Honnen,William;Pinter,Abraham;Weston,WarrenK;Harness,JaneA;Narayanan,Aarthi;Chang,TheresaL
• 通讯作者: Chang,TheresaL

Multifaceted immune functions of human defensins and underlying mechanisms.

人防御素和潜在机制的多方面免疫功能。

• DOI: 10.1016/j.semcdb.2018.02.023
• 发表时间: 2019-04
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Fruitwala S;El-Naccache DW;Chang TL
• 通讯作者: Chang TL

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

• DOI: 10.3390/v13060953
• 发表时间: 2021-05-21
• 期刊: Viruses
• 作者: Xu C;Wang A;Geng K;Honnen W;Wang X;Bruiners N;Singh S;Ferrara F;D'Angelo S;Bradbury ARM;Gennaro ML;Liu D;Pinter A;Chang TL
• 通讯作者: Chang TL