The State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, 100871, China.
Center for Quantitative Biology, Peking University, Beijing, 100871, China.
J Biol Phys. 2024 Jun;50(2):197-214. doi: 10.1007/s10867-024-09655-5. Epub 2024 Apr 20.
Time of day affects how well the immune system responds to viral or bacterial infections. While it is well known that the immune system is regulated by the circadian clock, the dynamic origin of time-of-day-dependent immunity remains unclear. In this paper, we studied the circadian control of immune response upon infection of influenza A virus through mathematical modeling. Dynamic simulation analyses revealed that the time-of-day-dependent immunity was rooted in the relative phase between the circadian clock and the pulse of viral infection. The relative phase, which depends on the time the infection occurs, plays a crucial role in the immune response. It can drive the immune system to one of two distinct bistable states, a high inflammatory state with a higher mortality rate or a safe state characterized by low inflammation. The mechanism we found here also explained why the same species infected by different viruses has different time-of-day-dependent immunities. Further, the time-of-day-dependent immunity was found to be abolished when the immune system was regulated by an impaired circadian clock with decreased oscillation amplitude or without oscillations.
昼夜节律会影响免疫系统对病毒或细菌感染的反应能力。虽然人们已经知道免疫系统受到生物钟的调节，但昼夜节律依赖性免疫的动态起源尚不清楚。在本文中，我们通过数学建模研究了流感病毒感染时免疫反应的昼夜节律控制。动态模拟分析表明，昼夜节律依赖性免疫源于生物钟和病毒感染脉冲之间的相对相位。相对相位取决于感染发生的时间，在免疫反应中起着至关重要的作用。它可以将免疫系统推向两种截然不同的双稳态之一，即炎症水平较高、死亡率较高的高炎症状态，或炎症水平较低的安全状态。我们在这里发现的机制也解释了为什么同一物种感染不同的病毒会产生不同的昼夜节律依赖性免疫。此外，当免疫系统受到生物钟调节受损、振荡幅度降低或没有振荡时，昼夜节律依赖性免疫会被消除。
