The Role of IL-27 in Controlling Persistent Viral Infection

IL-27 在控制持续病毒感染中的作用

• 批准号: 8897666
• 负责人: John Ross Teijaro
• 金额: $ 47.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897666
• 关键词: Acute; Affect; Animal Model; Antibodies; Antibody Formation; Antiviral Agents; Applications Grants; Arenavirus; B-Lymphocytes; Biological Response Modifiers; CD8B1 gene; Cell physiology; Cone; Defect; Development; Disease; Environment; Equilibrium; Family; Functional disorder; Generations; HIV; Health; Health Care Costs; Hepatitis B Virus; Hepatitis C virus; Human; IgG1; Immune; Immune response; Immunity; Immunoglobulin G; Immunosuppressive Agents; Infection; Interleukin-10; Interleukin-6; Lymphocytic choriomeningitis virus; Modeling; Mus; Nature; Outcome; Plasma; Play; Production; Public Health; Role; Signal Transduction; T cell response; T-Lymphocyte; Time; Translating; Vaccine Therapy; Viral; Virus; Virus Diseases; base; cytokine; exhaustion; in vivo; member; neglect; novel; purge; response; restoration; therapy design

DESCRIPTION (provided by applicant): Persistent virus infections cause disease in hundreds of millions of people and exert constant strain on the global economy due to healthcare costs. While progress has been made towards understanding mechanisms that allow viruses to persist, therapies to control persistent viruses are not optimal due an incomplete understanding of the factors involved in virus persistence. One common theme that accompanies virus persistence is an exhaustive or hypo-responsive state of adaptive immune response. This phenomenon was first described using the staple animal model for studying virus persistence, Lymphocytic Choriomeningitis Virus (LCMV), in its natural mouse host and extended to human persistent infections. Using this model, it was revealed that a balance between positive and negative immune regulatory molecules is essential to purge virus infection. One of the most extensively studied mechanisms contributing to virus persistence has been T cell exhaustion, which is potentiated by negative immune regulatory molecules such as IL-10 and PD-1. Interestingly, the absence of two positive immune regulatory molecules, IL-6 and IL-21, result in the inability to control persistent virus infection. These molecules are known to be important for B cell function. However, studies on whether B cells also control persistent virus infection have been neglected and their role remains unknown. A newly discovered member of the IL-6 family, IL-27, modulates both B and T cell responses during infection. However, few studies have examined how IL-27 affects antiviral immune responses. I began studying how IL-27 deletion affects the outcome of both acute and persistent LCMV infection. I made the observation that IL-27-deficiency resulted in prolonged LCMV clone-13 persistence. Prolonged virus persistence in IL-27-/- mice correlated with defects in both T and B cell responses. Virus specific T cells in IL- 27-/- mice displayed exacerbated T cell exhaustion following clone-13 infection. Moreover, I discovered that IL- 27-/- mice made elevated levels of IgG1 with minimal production of IgG2a, compared to predominant production of IgG2a in IL-27+/+ hosts. I further demonstrated that development of plasma B cells (the major antibody producers) and anti-LCMV IgG production is required to control clone-13 infection, indicating that antibody likely plays an important role in controlling persistent virus infection. This grant proposal aims to elucidate the mechanisms by which IL-27-deficiency leads to prolonged LCMV persistence. The aims are focused on understanding how IL-27 contributes to altered antiviral T and B cell responses and whether IL-27 signaling on T or B cells is essential to purge persistent LCMV infection. The absence of IgG2a production during persistent virus infection in IL-27-deficient mice suggests that IL-27- dependent induction of IgG2a may be essential to control persistent virus infection. The possibility that a specific antibody isotype may be essential to purge persistent virus infection i novel and will be investigated within this proposal.

描述（由申请人提供）：持续性病毒感染导致数亿人患病，并因医疗保健成本而对全球经济造成持续压力。虽然在理解允许病毒持续存在的机制方面取得了进展，但由于对病毒持续存在所涉及的因素的不完全理解，控制持续存在的病毒的疗法并不是最佳的。伴随病毒持续存在的一个共同主题是适应性免疫应答的耗尽或低应答状态。这种现象首先使用用于研究病毒持久性的主要动物模型淋巴细胞脉络丛脑膜炎病毒（LCMV）在其天然小鼠宿主中描述，并扩展到人类持续感染。使用该模型，揭示了阳性和阴性免疫调节分子之间的平衡对于清除病毒感染是必不可少的。导致病毒持续存在的最广泛研究的机制之一是T细胞耗竭，这是由负性免疫调节分子如IL-10和PD-1加强的。有趣的是，两种阳性免疫调节分子IL-6和IL-21的缺乏导致无法控制持续的病毒感染。已知这些分子对于B细胞功能是重要的。然而，关于B细胞是否也控制持续性病毒感染的研究一直被忽视，它们的作用仍然未知。IL-6家族的一个新发现的成员IL-27在感染期间调节B和T细胞应答。然而，很少有研究探讨IL-27如何影响抗病毒免疫反应。我开始研究IL-27缺失如何影响急性和持续性LCMV感染的结果。我观察到IL-27缺乏导致LCMV克隆-13持续时间延长。IL-27-/-小鼠中病毒持续时间延长与T和B细胞应答缺陷相关。IL-10中的病毒特异性T细胞 27-/-小鼠在克隆-13感染后表现出加剧的T细胞耗竭。此外，我发现，与IL-27+/+宿主主要产生IgG 2a相比，IL-27-/-小鼠产生的IgG 1水平升高，IgG 2a产生最少。我进一步证明了血浆B细胞（主要抗体产生者）的发育和抗LCMV IgG的产生是控制克隆-13感染所必需的，这表明抗体可能在控制持续性病毒感染中起重要作用。这项拨款提案旨在阐明IL-27缺乏导致LCMV持续时间延长的机制。目的是了解IL-27如何有助于改变抗病毒T和B细胞反应，以及T或B细胞上的IL-27信号传导是否对清除持续的LCMV感染至关重要。在IL-27缺陷小鼠中持续性病毒感染期间IgG 2a产生的缺乏表明IgG 2a的IL-27依赖性诱导对于控制持续性病毒感染可能是必不可少的。特异性抗体同种型可能对清除持续性病毒感染至关重要，这是一种新的可能性，将在本提案中进行研究。