Targeting the circadian clock to restore hepatitis B T-cell immunity

昼夜节律调节生理和新陈代谢过程的变化，使地球上的生物能够对日常环境要求和病原体暴露做出反应。宿主的先天和获得性免疫反应受昼夜节律调节，影响对病毒感染的易感性和对疫苗的反应。近年来，科学家们发现了支撑生物钟日常循环的遗传机制，这种生物钟在单个细胞中运行。此外，科学家们还发现了器官内不同细胞类型的生物钟之间的通讯，而且从基因上扰乱肝细胞的生物钟可以影响邻近免疫细胞的生物钟。因此，有理由相信生物钟控制着肝脏内的免疫，这对病毒保护至关重要。乙肝病毒只感染人类的肝脏，仍然是一个主要的健康问题，全世界每年有2.7亿人慢性感染，88万人死于包括肝硬变和癌症在内的肝病。目前的抗病毒药物减少了病毒负担，但不能治愈，也不能消除患肝癌的风险。慢性乙肝与抗病毒T细胞免疫低下有关，T细胞免疫无法控制病毒复制。因此，迫切需要根治疗法，了解导致这些T细胞缺陷的原因可以帮助设计和评估根治疗法。我们最近发现乙肝患者肝脏中时钟基因的中断，我假设这是感染肝脏中T细胞反应较差的原因。重要的是，我们最近的数据表明，通过药物操纵昼夜节律通路可以增强慢性乙型肝炎患者的乙肝病毒特异性T细胞的功能。因此，通过研究昼夜节律系统如何调节感染肝脏中的T细胞免疫，以及一天中的不同时间如何影响乙肝疫苗的效力，我们将发现T细胞恢复的新的治疗机会，并提高乙肝治疗性疫苗的疗效。在更广泛的背景下，有关组织和局部免疫之间时钟通讯的知识将适用于许多其他病原体。

Circadian rhythms regulate changes in physiological and metabolic processes which allow organisms on earth to respond to daily environmental demands and pathogenic exposure. Host innate and adaptive immune responses are circadian regulated and influence susceptibility to viral infection and response to vaccines. In recent years, scientists have discovered the genetic machinery that underpins the daily cycling of the circadian clock that operates in individual cells. Furthermore, scientists uncovered communications between circadian clocks of different cell types within an organ, and that genetically perturbing the clock in the hepatocytes can impact the clocks in their neighbouring immune cells. Therefore, there is reason to believe that the circadian clock controls immunity within the liver which is essential for viral protection. Hepatitis B virus (HBV) only infects the human liver and remains a major health problem with >270 million chronic infections and 880,000 deaths/year worldwide from liver disease including cirrhosis and cancer. Current antivirals reduce the viral burden but are not curative and do not remove the risk of liver cancer. Chronic hepatitis B is associated with poor anti-viral T-cell immunity that fails to control viral replication. Therefore, curative treatments are desperately needed, and understanding what causes these T-cell defects could aid the design and evaluation of curative therapies.We recently discovered a disruption of clock genes in the liver of HBV patients, which I hypothesise contributes to the poor T-cell response in the infected liver. Importantly, our recent data suggest that manipulation of circadian pathways by drugs can enhance the function of HBV-specific T-cells in CHB patients. Therefore by studying how the circadian system regulates T-cell immunity in the infected liver and how the time of day affects HBV vaccine efficacy, we will identify novel therapeutic opportunities for T-cell restoration and improve the efficacy of HBV therapeutic vaccines. In a broader context, knowledge of the communication of clocks between tissue and local immunity will be applicable to many other pathogens.