Role of interferon lambda in host protection during aging

干扰素 lambda 在衰老过程中宿主保护中的作用

• 批准号: 9764228
• 负责人: Rudragouda Channappanavar
• 金额: $ 19万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764228
• 关键词: Address; Aging; Antibody Formation; Antiviral Agents; Antiviral Response; Bacterial Infections; Blocking Antibodies; Cells; Chronic; Clinical; Clinical Trials; Coronavirus; Coronavirus Infections; Disease; Dose; Elderly; Epithelial; Epithelial Cells; Foundations; Gene Expression; Genes; Goals; Healthcare; Human; Immune; Immunobiology; Immunology; Impairment; In Vitro; Individual; Infection; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Interferon-alpha; Interferons; Kinetics; Knockout Mice; Life Expectancy; Lung; Middle East Respiratory Syndrome Coronavirus; Molecular Biology; Morbidity - disease rate; Murine hepatitis virus; Mus; Pathogenesis; Pathogenicity; Play; Pneumonia; Receptor Signaling; Recombinants; Respiratory System; Role; Route; SARS coronavirus; Severe Acute Respiratory Syndrome; Severity of illness; Source; Surface; Testing; Therapeutic; Therapeutic Agents; Translations; Treatment Efficacy; Virus Diseases; Virus Replication; adaptive immune response; age related; aged; aging population; base; cell age; chemokine; cytokine; experimental study; genome-wide; immune function; immunopathology; in vivo; interferon-alpha B; mortality; mouse model; older patient; prophylactic; receptor; respiratory; respiratory infection virus; response; side effect; therapeutic evaluation; viral RNA; virology

Project Summary (Abstract): The elderly are highly susceptible to a variety of virus infections. In particular, virus infections of the respiratory tract account for a substantial increase in morbidity and mortality in the aged individuals. Impaired innate and adaptive antiviral responses are, in part, responsible for increased disease severity in the elderly. Interferon (IFN) cytokines, specifically, type I IFN [IFN-ab] and type III IFNs [IFN-lambda (1-3, l)], constitute the first line of innate defense against virus infections. While IFN-ab response is protective, an excessive IFN-ab response may cause immunopathology and severe disease. In contrast, IFN-l is a non-redundant frontline antiviral cytokine that acts specifically on airway epithelial cells without causing excessive inflammation. Pathogenic human coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause severe disease in the elderly. Similarly, mouse adapted strains of SARS-CoV and mouse hepatitis virus- 1 (MHV-1, a pneumotropic mouse CoV) cause age-dependent increases in disease severity. Our preliminary results show that: a) IFN-l and interferon stimulated gene (ISG) expression is significantly reduced in the lungs of CoV-infected aged mice, and b) early therapeutic administration of IFN-l provides complete protection against lethal CoV infection in susceptible mice. In this project, we will characterize IFN-l and ISG responses, identify the source and investigate the mechanistic basis for impaired IFN-l and ISG response in SARS-CoV infected aged mice. Additionally, we will examine the role of IFN-l in host protection during aging, and test the prophylactic and therapeutic efficacy of recombinant-IFN-l (rIFN-l) in young (2 months) and aged (18-20 months) mice following intranasal infection with SARS-CoV. To address these goals, we will use immunology-, virology- and molecular biology-based in vitro and in vivo experiments. In vivo studies will include use of IFN-ab receptor (IFNAR) and IFN-l receptor (IFNLR) blocking antibodies and of WT, IFNAR-/- and IFNLR -/- mice. Our goal is to establish IFN-l as a potential therapeutic agent for treating respiratory virus infections in the elderly. Since CoVs induce age-dependent respiratory illness both in humans and in mice, we believe that aged mice infected with CoV are an ideal platform for studying the immunobiology of respiratory virus infections in the elderly. The results obtained from this study will provide a foundation for testing therapeutic potential of rIFN-l in CoV and other respiratory virus infections.

项目摘要（Abstract）： 老年人对各种病毒感染高度敏感。特别是， 呼吸道是老年人发病率和死亡率显著增加的原因。 先天性和适应性抗病毒反应受损是疾病严重程度增加的部分原因 在老年人中。干扰素（IFN）细胞因子，特别是I型IFN [IFN-ab]和III型IFN [IFN-lambda (1-3，l）]，构成了抵抗病毒感染的第一道先天防御。虽然IFN-ab反应是 保护性的，过度的IFN-ab应答可能导致免疫病理学和严重的疾病。与此相反， IFN-1是一种非冗余的前线抗病毒细胞因子，其特异性作用于气道上皮细胞，而不影响细胞增殖。 导致过度炎症。病原性人类冠状病毒（CoV），如严重急性 呼吸综合征冠状病毒（SARS-CoV）和中东呼吸综合征冠状病毒（MERS-CoV） 老年人的严重疾病。类似地，SARS-CoV和小鼠肝炎病毒的小鼠适应株- 1（MHV-1，一种嗜肺小鼠CoV）引起疾病严重程度的年龄依赖性增加。我们 初步结果显示：a）IFN-1和干扰素刺激基因（ISG）表达显著增加， 在CoV感染的老年小鼠的肺中减少，和B）IFN-1的早期治疗性施用 在易感小鼠中提供针对致死CoV感染的完全保护。在这个项目中，我们将 表征IFN-1和ISG应答，鉴定来源并研究IFN-1和ISG应答的机制基础。 SARS-CoV感染老年小鼠IFN-1和ISG应答受损。此外，我们将研究 IFN-1在衰老过程中宿主保护中的作用，并测试IFN-1的预防和治疗功效。 重组IFN-1（rIFN-1）在年轻（2个月）和老年（18-20个月）小鼠中鼻内给药后的变化 感染SARS-CoV。为了实现这些目标，我们将使用免疫学、病毒学和分子生物学。 基于生物学的体外和体内实验。体内研究将包括使用IFN-ab受体 图1显示了IFN-1受体（IFNAR）和IFN-I受体（IFNLR）阻断抗体以及WT、IFNAR-/-和IFNLR -/-小鼠的免疫组化结果。我们 目的是建立IFN-1作为治疗呼吸道病毒感染的潜在治疗剂， 老人由于冠状病毒在人类和小鼠中都会诱导年龄依赖性呼吸道疾病，我们相信， 感染CoV的老年小鼠是研究呼吸道疾病免疫生物学的理想平台。 老年人的病毒感染本研究所获得的结果将为测试提供依据 rIFN-1在CoV和其它呼吸道病毒感染中的治疗潜力。