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

昼夜节律调节生理和代谢过程的变化，使地球上的生物体能够对日常环境需求和病原体暴露做出反应。宿主的先天性和适应性免疫应答受昼夜节律调节，并影响对病毒感染的易感性和对疫苗的应答。近年来，科学家们发现了支持个体细胞中生物钟日常循环的遗传机制。此外，科学家们发现了器官内不同细胞类型的生物钟之间的通信，并且遗传干扰肝细胞中的生物钟可以影响其邻近免疫细胞中的生物钟。因此，有理由相信生物钟控制肝脏内的免疫力，这对病毒保护至关重要。B型肝炎病毒（HBV）仅感染人类肝脏，并且仍然是一个主要的健康问题，全世界每年有> 2.7亿慢性感染和880，000人死于肝病，包括肝硬化和癌症。目前的抗病毒药物降低了病毒负荷，但不能治愈，也不能消除肝癌的风险。慢性B型肝炎与抗病毒T细胞免疫力低下有关，无法控制病毒复制。因此，迫切需要治愈性治疗，了解导致这些T细胞缺陷的原因可以帮助设计和评估治愈性疗法。我们最近发现HBV患者肝脏中的时钟基因被破坏，我假设这有助于感染肝脏中T细胞反应不良。重要的是，我们最近的数据表明，通过药物操纵昼夜节律途径可以增强CHB患者HBV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受感染肝脏中的T细胞免疫以及一天中的时间如何影响HBV疫苗效力，我们将确定T细胞恢复的新治疗机会并提高HBV治疗性疫苗的效力。在更广泛的背景下，组织和局部免疫之间的时钟通信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.