IL-27 elicited antibodies: A novel means to control persistent Arenavirus infection

 描述(申请人提供)：持续的病毒感染导致数亿人患病，并因医疗成本而给全球经济带来持续的压力。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的因素了解不完全，控制持续病毒的治疗方法并不是最佳的。伴随病毒持久性的一个共同主题是适应性免疫反应的穷尽或低反应状态。这一现象首次被用来研究病毒持久性的主要动物模型--淋巴细胞性脉络膜脑膜炎病毒(LCMV)在其自然小鼠宿主中描述，并推广到人类持续性感染。利用这一模型，揭示了正负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机制之一是T细胞耗竭，这种机制被IL-10和PD-1等负面免疫调节分子加强。有趣的是，缺乏两个积极的免疫调节分子，IL-6和IL-21，导致无法控制持续的病毒感染。众所周知，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病毒感染的研究一直被忽视，它们的作用仍不清楚。IL-6家族的一个新成员，IL-27，在感染过程中调节B和T细胞的反应。然而，很少有研究研究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 Clone-13持续时间延长。IL-27-/-小鼠体内病毒持续时间的延长与T和B细胞反应的缺陷有关。IL-1细胞中的病毒特异性T细胞 27-/-小鼠在感染Clone-13后表现出T细胞衰竭加剧。此外，我发现，与IL-27+/+宿主的主要IgG2a产生相比，IL-27-/-小鼠产生的IgG1水平较高，但产生的IgG2a最少。我进一步论证了控制Clone-13感染需要发展血浆B细胞(主要产生抗体)和产生抗LCMV Ig G，表明抗体可能在控制持续病毒感染中起重要作用。这项资助计划旨在阐明IL-27缺乏导致LCMV持续时间延长的机制。其目的集中在了解IL-27如何促进T和B细胞抗病毒反应的改变，以及T细胞或B细胞上的IL-27信号是否对清除持续的LCMV感染至关重要。在IL-27缺陷小鼠持续病毒感染期间没有产生IgG2a，这表明IL-27依赖的IgG2a诱导可能是控制持续病毒感染的关键。一种特定的抗体亚型可能是清除持续病毒感染的关键，这一可能性是新的，并将在本提案中进行调查。

 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.