GP130 Signaling During Chronic Virus Infection

慢性病毒感染期间的 GP130 信号传导

• 批准号: 8496709
• 负责人: Elina I Zuniga
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496709
• 关键词: Ablation; Acute; Antibodies; Antibody Formation; Antiviral Agents; Appearance; Arenavirus; Attenuated; B-Lymphocytes; BCL6 gene; Biological; Biological Models; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Differentiation process; Cells; Chimera organism; Chronic; Cytokine Signaling; Data; Defect; Environment; Family; Genes; HIV; HIV-1; Health; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Human; IL6 gene; Immune; Immune response; Immune system; Immunity; Immunology; Immunotherapy; In Vitro; Infection; Interleukin-10; Interleukin-6; Knowledge; Lead; Link; Lymphocytic choriomeningitis virus; Measures; Modeling; Molecular; Monitor; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Play; Population; Production; Regulation; Reporting; Research; Resolution; Rodent; Role; Science; Signal Pathway; Signal Transduction; Staging; Structure of germinal center of lymph node; Surface; T cell response; T-Lymphocyte; Time; Transgenic Organisms; Translating; Up-Regulation; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Whole Organism; adaptive immunity; base; cytokine; exhaustion; fighting; in vivo; insight; interleukin-21; nonhuman primate; novel; prevent; receptor; research study; response; small hairpin RNA; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Multiple inhibitory molecules create a profoundly immunuosuppressive environment that is conserved among chronic viral infections and makes eliciting effective immunity challenging. Human persistent viruses highly relevant to health, including HIV, HCV and HBV are restricted to human and non- human primates, which poses great limitations and difficulties to experimental based research. The complexity of the immune system cannot be accurately recreated in vitro and its study requires the use of appropriate whole organisms. We have therefore chosen to use chronic lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, as a model system. In a previous study, we found that interleukin-6 (IL- 6) is produced in a unique biphasic manner during persistent LCMV infection and that late IL-6 escalates T follicular helper responses, being essential for viral control (Harker et al. Science 2011). IL6 shares the transducing co-receptor gp130 with the IL6 family of cytokines of which four have been related to the immune system. Our preliminary studies indicate that ablation of gp130 in T cells during chronic LCMV infection resulted in more profound defects than the sole absence of IL6 signaling, as indicated by reduction of virus-specific CD4 T cell numbers and their IL-21 secretion (in addition) to diminished Tfh responses. These data indicate that gp130 signaling cytokines, including but not limited to IL6, play a central role in orchestrating CD4 T cells responses and resolving persistent LCMV infection in vivo. We propose to investigate the role of gp130 signaling cytokines (other than IL-6) and their mechanistic link to CD4 T cell responses during chronic LCMV infection. In Aim #1 we will study gp130flox/flox mice to investigate the role of gp130 signaling at different times and in specific cell populations during chronic LCMV infection. We will determine the mechanism underlying gp130 control of CD4 T cell numbers by measuring survival and proliferation in mixed bone marrow chimeras. In Aim 2 we will explore the levels of and CD4 T cell responsiveness to gp130-cytokines (other than IL6) and we will use shRNA and/or genetically modified mice to investigate their function during chronic LCMV infection. Studies in the past three decades using LCMV murine infection have demonstrated high conservation in the immune responses against persistent viruses in mouse and humans. Therefore the knowledge gained from the proposed experiments will not only enhance our understanding of basic immunology but also point out important players that could regulate immune responses and represent therapeutic targets during chronic viral infections in humans. Furthermore, since LCMV is considered a prototypic arenavirus the proposed studies will increase our understanding of the pathogenesis of human arenaviruses, which cause fatal hemorrhagic fevers.

描述（由申请人提供）：多种抑制性分子产生了一种在慢性病毒感染中保守的深度免疫抑制环境，并使引发有效免疫具有挑战性。与健康高度相关的人类持久性病毒（包括HIV、HCV和HBV）仅限于人和非人灵长类动物，这给基于实验的研究带来了很大的限制和困难。免疫系统的复杂性无法在体外准确重现，其研究需要使用适当的完整生物体。因此，我们选择使用慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的自然宿主，小鼠，作为模型系统。在先前的研究中，我们发现在持续性LCMV感染期间以独特的双相方式产生白细胞介素-6（IL- 6），并且晚期IL-6使T滤泡辅助应答升级，这对于病毒控制是必不可少的（Harker等人，Science 2011）。IL 6与IL 6细胞因子家族共享转导共受体gp 130，其中四种细胞因子与免疫系统相关。我们的初步研究表明，在慢性LCMV感染过程中，T细胞中gp 130的消融导致比单纯缺乏IL 6信号传导更严重的缺陷，如通过减少病毒特异性CD 4 T细胞数量及其IL-21分泌（此外）减少Tfh应答所示。这些数据表明，gp 130信号传导细胞因子，包括但不限于IL 6，在协调CD 4 T细胞应答和解决体内持续LCMV感染中发挥核心作用。我们建议调查的作用gp 130信号细胞因子（IL-6以外）和他们的机械联系，在慢性LCMV感染的CD 4 T细胞反应。在目标#1中，我们将研究gp 130 flox/flox小鼠，以研究gp 130信号传导在慢性LCMV感染期间不同时间和特定细胞群中的作用。我们将通过测量混合骨髓嵌合体的存活和增殖来确定gp 130控制CD 4 T细胞数量的机制。在目标2中，我们将探索水平和CD 4 T细胞对gp 130-细胞因子（IL 6除外）的反应性，我们将使用shRNA和/或遗传修饰小鼠来研究它们在慢性LCMV感染期间的功能。在过去三十年中，使用LCMV小鼠感染的研究已经证明了小鼠和人类中针对持久性病毒的免疫应答的高度保守性。因此，从拟议的实验中获得的知识不仅将增强我们对基础免疫学的理解，而且还将指出可以调节免疫反应并代表人类慢性病毒感染期间的治疗靶点的重要参与者。此外，由于LCMV被认为是一种原型沙粒病毒，因此拟议的研究将增加我们对人类沙粒病毒致病机制的理解，这种病毒会导致致命的出血热。