氨基酸信号通过Rag GTPase在生发中心调控新冠病毒感染及疫苗免疫应答的研究

生发中心免疫应答与抗SARS-CoV-2体液免疫的形成有着密切的关系。然而，氨基酸信号与生发中心抗病毒免疫应答研究尚属空白。我们已发表的研究及前期实验显示，SARS-CoV-2感染后小鼠淋巴结CD4+T细胞氨基酸信号传导异常，Rag GTPase家族是氨基酸信号感应的关键节点，其缺失会导致GC-Tfh发育及功能行使受损。本项目拟利用单细胞测序联合氨基酸代谢组学分析揭示SARS-CoV-2感染后生发中心氨基酸代谢与免疫应答的关系；解析氨基酸信号通过 Rag GTPase在生发中心调控免疫应答的具体分子生物学机制；验证通过增强氨基酸信号促进GC-Tfh发育成熟调控体液免疫应答；并评估氨基酸增强型佐剂促进纳米颗粒疫苗在小鼠及恒河猴体内疫苗免疫响应的能力。本项目为SARS-CoV-2感染免疫干预及监测提供新的策略，基于生发中心代谢免疫学提出合理并经济有效的增强型疫苗佐剂，为疫苗临床应用提供理论基础

Immune responses taken place in the germinal center (GC) is closely intertwined with the development of anti-SARS-CoV-2 humoral responses. However, the role played by amino acid signal in GC anti-viral immune response remain elusive. Our publications and preliminary data together demonstrate the abnormality of multiple amino acid transporter expression in immune cells residing in GC of SARS-CoV-2 infected mice; Rag GTPase family proteins are rendered unfunctional in the absence of amino acid signals, which inhibits the development and functionality of GC-Tfh cells. In this study, we propose to take advantage of the single-cell sequence in combination with amino acid metabolome analysis to reveal the relationship of GC amino acid metabolism and immune response during SARS-CoV-2 infection. We will further delineate the molecular mechanism of how amino acid signal regulate immune response in GC via Rag GTPase. The hypothesis of boosting the GC-Tfh development by elevated amino acid signals supply in order to regulate humoral immune response will be validated. Last but not least, we will investigate the therapeutic efficacy of enhanced amino acid supply as adjuvant to novel SARS-CoV-2 nanoparticle vaccine in hACE2-transgeneic mice and rhesus macaques. Based on the germinal center metabolic immunology, the completion of this study will provide new insights into the intervention and monitoring of anti-SARS-CoV-2 immune responses, as well as lending theoretical and practical evidences to the development of clinical application of novel vaccines with effective and economic adjuvants.