Novel Strategies for Controlling Persistent Viral Infection

控制持续病毒感染的新策略

基本信息

批准号：
9248857
负责人：
John Ross Teijaro
金额：
$ 48.13万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248857
关键词：
Address Antibodies Antibody Formation Antibody Response Antiviral Agents Architecture B-Lymphocytes Biochemical Pathway Biological Response Modifiers Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Differentiation process Cell physiology Cells Chimera organism Complement Data Development Environment Equilibrium Future Generations Genetic Goals Grant HIV/HCV Helper-Inducer T-Lymphocyte Hepatitis B Human Humoral Immunities IFNAR1 gene Immune Immune response Immune system Immunosuppression Impairment Infection Interferons Interleukin-10 Interleukin-6 Knowledge LoxP-flanked allele Lymphocytic choriomeningitis virus Lymphoid Lymphoid Tissue Mediating Modality Modeling Molecular Mus Natural Killer Cells Output PDCD1LG1 gene Partner in relationship Plasma Plasma Cells Play Public Health Publishing Reporting Role Signal Pathway Signal Transduction Structure of germinal center of lymph node T-Lymphocyte Time Transcriptional Activation Translational Research Viral Virus Virus Diseases base biochemical tools exhaustion in vivo neutralizing antibody novel strategies prevent public health relevance purge receptor response therapeutic development transcription factor

项目摘要

DESCRIPTION (provided by applicant): Persistent viral infections represent a significant public health problem with hundreds of millions of people infected. However, therapies that enable the host to purge these infections have been unsuccessful due to a limited understanding of the cellular and molecular mechanisms that promote virus persistence. Over the last decade studies have demonstrated that persistent viruses take advantage of negative immune regulatory molecules (IL-10, PD-1) to suppress the antiviral CD4 and CD8 T cell responses, resulting in T cell exhaustion, enabling virus persistence. Deletion of several immune stimulatory molecules such as IL-6 and IL- 21 result in lifelong virus persistence, suggest that the balance between negative and positive immune regulators determines virus clearance or persistence. Importantly, molecules such as IL-6 and IL-21 have known T follicular helper cell (TFH) and B cell stimulatory capacities and depletion of these molecules in vivo results in reduced TFH, B cell responses and antibody production. In fact, studies in humans have demonstrated that although TFH and germinal center (GC) B cells are generated during human persistent virus infection, their function is impaired. Despite the above findings, the mechanisms that restrain/promote optimal TFH, B and antibody responses during persistent virus infection are incompletely understood. We recently made the unexpected finding that during persistent LCMV infection IFN-I signaling was essential to promoting (rather than preventing) virus persistence. Importantly, IFN-I signaling supported induction of negative immune regulators (NIR) IL-10 and PD-L1, immune suppression, T cell exhaustion and lymphoid tissue destruction. Following up our published studies we now report that blockade of IFN-I signaling results in enhanced TFH, GC and plasma B cell responses. Thus we hypothesize IFN-I signaling restrains antiviral humoral immunity during persistent virus infection. The ultimate goal of this proposal is to generate a detailed understanding how IFN-I signaling modulates immune responses during persistent virus infection. The output of our studies should be a detailed cellular and molecular understanding how IFN-I regulates anti-viral humoral and cellular immune responses during persistent virus infection. In this project will use anti-IFNAR1 neutralizing antibodies, genetic and biochemical tools to determine how IFNAR1 signaling regulates TFH, GC and plasma B cell responses during a model persistent virus infection. This proposal encompasses important basic and potentially translational research goals - 1) to understand the mechanisms by which IFNAR1 signaling suppresses immune cell function; 2) discover IFN-I regulated cellular and biochemical pathways that promote virus persistence; and 3) leverage this knowledge to instruct future development of therapeutic modalities to promote immune responses to control of human persistent viral infection.

描述（由申请人提供）：持续性病毒感染是一个重大的公共卫生问题，有数亿人受到感染。然而，由于对病毒感染的细胞和分子机制的了解有限，使宿主能够清除这些感染的疗法一直不成功。过去十年的研究表明，持久性病毒利用阴性免疫调节分子（IL-10、PD-1）来抑制抗病毒 CD4 和 CD8 T 细胞反应，导致 T 细胞耗竭，从而使病毒得以持久存在。。 IL-6和IL-21等多种免疫刺激分子的缺失会导致病毒终生持续存在，这表明阴性和阳性免疫调节剂之间的平衡决定了病毒的清除或持续存在。已知滤泡辅助细胞 (TFH) 和 B 细胞的刺激能力和体内这些分子的消耗会导致 TFH、B 细胞反应和抗体产生减少。尽管有上述发现，但在持续病毒感染期间抑制/促进最佳 TFH、B 和抗体反应的机制尚不完全清楚。研究发现，在持续性 LCMV 感染期间，IFN-I 信号传导对于促进（而不是阻止）病毒持续存在至关重要。重要的是，IFN-I 信号传导支持负性免疫调节因子 (NIR) IL-10 和 PD-L1、免疫抑制、T 细胞的诱导。精疲力竭和继我们发表的研究之后，我们现在报道，阻断 IFN-I 信号传导会增强 TFH、GC 和血浆 B 细胞反应，因此我们帮助 IFN-I 信号传导抑制持续病毒感染期间的抗病毒体液免疫。该提案的最终目标是详细了解 IFN-I 信号如何在持续病毒感染期间调节免疫反应。我们研究的成果应该是详细的细胞和分子了解 IFN-I 如何调节抗病毒体液和细胞免疫。在该项目中，将使用抗 IFNAR1 中和抗体、遗传和生化工具来确定 IFNAR1 信号如何在模型持续病毒感染期间调节 TFH、GC 和血浆 B 细胞反应。潜在的转化研究目标 - 1）了解 IFNAR1 信号传导抑制免疫细胞功能的机制；2）发现促进病毒持久性的 IFN-I 调节细胞和生化途径；3）利用这些知识指导未来治疗方法的开发促进免疫反应以控制人类持续性病毒感染。