Role of IFNe in immune modulation and HIV infection

IFNe在免疫调节和HIV感染中的作用

基本信息

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
项目类别：
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

项目摘要

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）是一个关键的先天免疫介质，可保护宿主免受性传播感染。尽管当前的范例是IFNε是I型IFN，并通过IFNA受体发出信号，但我们其他已发表的结果表明，IFNε具有与IFNA/b不同的独特免疫功能。 IFNε是高度丰富的女性生殖道的粘膜，具有优质的粘膜免疫活性与IFNA/b相比。 ifne基因表达受雌激素，细胞因子和半等化的调节，但不是由Toll样受体途径诱导，诱导IFNA/b。临床证据表明保护作用反对艾滋病毒的ifne。 IFNE表达在月经周期中与雌激素水平呈正相关，并且与HIV敏感性成反比。重要的是，经常接触的HIV负性性工作者精液的IFNE基因表达水平升高，免疫效应子的数量增加宫颈组织中的细胞。我们最近证明IFNE通过一种机制影响了反HIV状态独立于原发性巨噬细胞中已知的I型IFN诱导的HIV宿主限制因子。此外，与IFNA2相比，IFNε具有更健壮的免疫响应。我们假设是，如果IFNE在通过保护艾滋病毒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的免疫力学及其对体外，宫颈外植体对HIV感染的影响人源化的小鼠模型。为了更好地了解IFNE介导的HIV的分子机制抑制作用，我们确定病毒确定剂对IFNE敏感性很重要。因为已知雌激素调节IFNE表达和粘膜免疫，我们将评估雌激素对IFNε介导的影响雌激素治疗前后绝经后妇女的HIV感染过程。阐明 ifne的特性和功能有望扩大我们对艾滋病毒至关重要的病毒宿主相互作用的知识预防和控制病毒储层和免疫病变。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
作者：
Xu C;Wang A;Hoskin ER;Cugini C;Markowitz K;Chang TL;Fine DH
通讯作者：
Fine DH

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

DOI：
10.1002/jlb.2ce1120-733r
发表时间：
2021-05
期刊：
Journal of leukocyte biology
影响因子：
5.5
作者：
Xu C;Chang TL
通讯作者：
Chang TL

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。

DOI：
发表时间：
2022
期刊：
EC microbiology
影响因子：
0
作者：
Xu,Chuan;Wang,Annie;Honnen,William;Pinter,Abraham;Weston,WarrenK;Harness,JaneA;Narayanan,Aarthi;Chang,TheresaL
通讯作者：
Chang,TheresaL

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
影响因子：
0
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

Multifaceted immune functions of human defensins and underlying mechanisms.