The Role of IL-27 in Controlling Persistent Viral Infection

描述（由申请人提供）：持续的病毒感染导致数亿人患病，并因医疗费用对全球经济造成持续压力。虽然在了解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的因素了解不完全，控制持续存在病毒的治疗方法并不是最佳的。伴随病毒持续存在的一个共同主题是适应性免疫反应的穷尽或低反应状态。这种现象最初是用研究病毒持久性的主要动物模型——淋巴细胞性脉络丛脑膜炎病毒（LCMV）在其天然小鼠宿主中描述的，并扩展到人类持久性感染。利用该模型，揭示了正、负免疫调节分子之间的平衡对清除病毒感染至关重要。目前研究最广泛的病毒持久性机制之一是T细胞耗竭，这是由负性免疫调节分子如IL-10和PD-1增强的。有趣的是，缺乏两种阳性免疫调节分子，IL-6和IL-21，导致无法控制持续病毒感染。这些分子对B细胞的功能很重要。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，其作用仍然未知。新发现的IL-6家族成员IL-27在感染过程中调节B细胞和T细胞的反应。然而，很少有研究调查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。病毒在IL-27-/-小鼠体内持续时间的延长与T细胞和B细胞反应缺陷相关。IL-中的病毒特异性T细胞

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.