Positive Immune-regulators During Chronic Viral Infections

慢性病毒感染期间的积极免疫调节剂

• 批准号: 10463620
• 负责人: Elina I Zuniga
• 金额: $ 55.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463620
• 关键词: Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Antiviral Response; Attenuated; Automobile Driving; B-Lymphocytes; Bacteria; Biological Models; Biological Response Modifiers; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Survival; Cells; Cessation of life; Chronic; Clostridium; Data; Development; Distal; Docosahexaenoic Acids; Elements; Environment; Exhibits; Farm; Goals; HIV; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immunity; Infection; Interleukin-6; Knowledge; Laboratories; Laboratory mice; Lymphocytic choriomeningitis virus; Mus; Pathway interactions; Phylogenetic Analysis; Production; Regulation; Reporting; Research; Rodent; Role; Serum; Site; Small Intestines; Specificity; T cell differentiation; T cell response; T-Lymphocyte; Testing; The Jackson Laboratory; Therapeutic; Time; Viral; Virus; Virus Diseases; base; burden of illness; chronic infection; cytokine; exhaustion; fighting; host microbiota; immunoregulation; in vivo; interleukin-21; metabolomics; microbiome; microbiota; mouse model; nonhuman primate; pathogen; prevent; progenitor; programmed cell death protein 1; programs; receptor

ABSTRACT Immune stimulatory pathways are dysregulated during chronic viral infections, preventing timely T cell and antibody mediated immunity. Human persistent viruses, including human immunodeficiency virus (HIV), hepatitis C and B viruses (HCV and HBV) cause tremendous disease burden worldwide but are restricted to human and nonhuman primates, which in turn poses great limitations for experimental-based research. Importantly, lymphocytic choriomeningitis virus (LCMV) in its natural rodent host has been successfully used as a model system to uncover common principles underlying the regulation of immune responses during persistent viral infections, often highlighting basic mechanisms that were later extended into humans. We have found that interleukin-6 (IL-6) and IL-27 are essential for optimal CD4 T cell differentiation and CD4 T cell survival, respectively, while they redundantly induce IL-21, a critical factor for CD8 T cell and antibody responses, late after infection. Consistently, both IL-6 and IL-27 were absolutely required to control chronic (but not acute) LCMV infection. More recent data indicate that late IL-27 derived from B cells is crucial for viral control and it is regulated by host microbiota during chronic LCMV infection. The overall goal of the current proposal is to fully dissect the mechanisms underlying the antiviral effects of B-cell-derived IL-27 as well as its regulation by host microbiota and related metabolites during persistent infection. To accomplish this goal, we propose three specific aims. In Aim 1 we will investigate the relationship between B-cell-derived IL-27 and antiviral responses during chronic LCMV infection. We will test the hypothesis that B cell-derived-IL-27 is both a dependent and a driver of CD4 T cell responses during chronic infection, and indirectly enhances antibodies and CD8 T cells, promoting viral control late after infection. In Aim 2 we will identify the microbiome commensals that enhance IL-27 production by B cells and the impact for antiviral responses and viral control during chronic LCMV infection. We will investigate the possibility that Segmented Filamentous Bacteria (SFB), a commensal that associates with accelerated viral control, enhances IL-27 production by B cells in small intestine as well as T cell responses both locally and at distal sites, overriding the need for IL-6. Finally, in Aim 3 we will identify microbiota-related metabolites that modulate IL-27 production by B cells and the impact for antiviral responses and viral control during chronic LCMV infection. We will investigate the metabolites that associate with the microbiota driving IL-27 production by B cells and evaluate their effects on IL-27 expression (in mouse and human B cells) as well as T cell responses and viral control in LCMV chronically infected mice. The knowledge gained from this study will not only enhance our understanding of the basic biology of key immune regulators (i.e. IL-27, microbiome and related metabolites) but may also be valuable for therapeutically manipulating these factors during infections and perhaps other immune diseases.

抽象的 慢性病毒感染期间免疫刺激途径失调，阻碍 T 细胞及时发挥作用 和抗体介导的免疫。人类持久性病毒，包括人类免疫缺陷病毒（HIV）、 丙型肝炎病毒和乙型肝炎病毒（HCV 和 HBV）在全世界造成巨大的疾病负担，但仅限于 人类和非人类灵长类动物，这反过来又给基于实验的研究带来了很大的限制。 重要的是，淋巴细胞脉络膜脑膜炎病毒（LCMV）在其天然啮齿动物宿主中已被成功使用 作为模型系统来揭示免疫反应调节的共同原理 持续的病毒感染，通常强调后来扩展到人类的基本机制。 我们发现白细胞介素 6 (IL-6) 和 IL-27 对于最佳 CD4 T 细胞分化和 CD4 T 细胞至关重要 细胞存活，同时它们过度诱导 IL-21，这是 CD8 T 细胞和抗体的关键因素 感染后晚期的反应。一致地，IL-6 和 IL-27 都是控制慢性疾病所必需的。 （但非急性）LCMV 感染。最近的数据表明，源自 B 细胞的晚期 IL-27 对于病毒至关重要 在慢性 LCMV 感染期间，它受到宿主微生物群的调节。当前的总体目标 建议全面剖析 B 细胞来源的 IL-27 抗病毒作用的机制： 以及持续感染过程中宿主微生物群和相关代谢物的调节。到 为实现这一目标，我们提出三个具体目标。在目标 1 中，我们将研究之间的关系 慢性 LCMV 感染期间 B 细胞衍生的 IL-27 和抗病毒反应。我们将检验假设 B 细胞衍生的 IL-27 在慢性感染期间既是 CD4 T 细胞反应的依赖性又是驱动因素，并且 间接增强抗体和 CD8 T 细胞，促进感染后期的病毒控制。在目标 2 中，我们将 确定增强 B 细胞产生 IL-27 的微生物组共生体及其影响 慢性 LCMV 感染期间的抗病毒反应和病毒控制。我们将调查以下可能性 分段丝状细菌 (SFB) 是一种与加速病毒控制相关的共生菌，可增强 小肠中 B 细胞产生 IL-27 以及局部和远端部位的 T 细胞反应， 超越对 IL-6 的需要。最后，在目标 3 中，我们将识别微生物相关的代谢物 调节 B 细胞产生 IL-27 及其对抗病毒反应和病毒控制的影响 慢性 LCMV 感染。我们将研究与驱动 IL-27 的微生物群相关的代谢物 B 细胞的产生并评估其对 IL-27 表达（在小鼠和人类 B 细胞中）以及 T 细胞的影响 LCMV 慢性感染小鼠的细胞反应和病毒控制。 从这项研究中获得的知识不仅将增强我们对基础生物学的理解 关键的免疫调节剂（即 IL-27、微生物组和相关代谢物），但也可能对 在感染和其他免疫疾病期间治疗性地操纵这些因素。