Positive Immune-regulators During Chronic Viral Infections

摘要 免疫刺激途径在慢性病毒感染期间失调，阻止及时的T细胞 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（艾滋病毒）， 丙型肝炎和B型肝炎病毒（HCV和HBV）在世界范围内引起巨大疾病负担，但仅限于 人类和非人类灵长类动物，这反过来又对基于实验的研究造成了很大的限制。 重要的是，淋巴细胞性脉络丛脑膜炎病毒（LCMV）在其天然啮齿类宿主中已成功地用于 作为一个模型系统，揭示免疫反应调节的共同原则， 持续的病毒感染，往往突出的基本机制，后来扩展到人类。 我们已经发现白细胞介素-6（IL-6）和IL-27对于最佳的CD 4 T细胞分化和CD 4 T细胞增殖是必需的。 细胞存活，同时它们冗余地诱导IL-21，这是CD 8 T细胞和抗体的关键因子 反应，感染后晚期。因此，IL-6和IL-27是控制慢性炎症的绝对必要条件。 (but非急性）LCMV感染。最近的数据表明，来自B细胞的晚期IL-27对于病毒感染是至关重要的。 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 这项研究的目的是充分剖析B细胞来源的IL-27的抗病毒作用的机制， 以及在持续感染期间宿主微生物群和相关代谢物对其的调节。到 为了实现这一目标，我们提出了三个具体目标。在目标1中，我们将研究 慢性LCMV感染期间B细胞衍生的IL-27和抗病毒应答我们将检验这个假设 B细胞衍生的IL-27是慢性感染期间CD 4 T细胞应答的依赖者和驱动者，并且 间接增强抗体和CD 8 T细胞，促进感染后后期的病毒控制。在目标2中， 确定增强B细胞产生IL-27的微生物组成分，以及 慢性LCMV感染期间的抗病毒应答和病毒控制。我们会调查 分段丝状细菌（SFB），一种与加速病毒控制相关的细菌， 小肠中B细胞的IL-27产生以及局部和远端部位的T细胞应答， 而不需要IL-6最后，在目标3中，我们将鉴定微生物相关的代谢物， 调节B细胞产生IL-27，以及在 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 通过B细胞产生IL-27，并评估它们对IL-27表达（在小鼠和人B细胞中）以及T细胞的影响。 LCMV慢性感染小鼠的细胞应答和病毒控制。 从这项研究中获得的知识不仅将提高我们对生物学的基本认识， 关键免疫调节剂（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子。

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.