Circadian Clock Gene Modulation and Selective Reprogramming in Response to Virus Infection
The circadian clock regulates fundamental cellular processes that include the host response to infection. However, the intersection of the circadian clock and the mechanisms that drive antiviral immunity remains poorly understood. Copy-back viral genomes (cbVGs) generated during virus replication strongly stimulate immunity during infection with negative-sense RNA viruses. Here, we demonstrate at…
Circadian clock genes play a crucial role in regulating various cellular functions, including the host's response to infection. However, the relationship between the circadian clock and the antiviral immune system is not fully understood. Recent research utilizing A549 lung epithelial cells, a commonly used model for lung infections, has shed light on this complex interaction.
It was discovered that upon infection with Sendai virus (SeV), A549 cells maintain their circadian rhythms and undergo a process of circadian clock remodeling primarily driven by an innate immune response triggered by the viral genome. This remodeling is mediated through two distinct pathways: the RIG-I adaptor MAVS pathway and the double-stranded RNA sensor PKR pathway.
The MAVS pathway is responsible for the preferential induction of the BMAL1 paralog ARNTL2, while the PKR pathway facilitates the induction of negative-feedback regulators such as NR1D1, NR1D2, and PER1.
Interestingly, a similar pattern of cbVG-driven circadian gene regulation was observed during respiratory syncytial virus infection, indicating that this phenomenon is not unique to SeV. To further investigate the role of ARNTL2, gain- and loss-of-function experiments were conducted. These experiments demonstrated that ARNTL2 is functionally essential for amplifying the transcriptional response to infection, particularly in the expression of specific antiviral genes like CCL5.
In summary, this groundbreaking study establishes that innate immune signaling triggered by viral copy-back genomes (cbVGs) plays a selective role in driving circadian clock gene expression during viral infection. By utilizing distinct sensing pathways and identifying ARNTL2 as a previously unrecognized regulator of virus-induced host transcriptional responses, this research provides valuable insights into the intricate relationship between the circadian clock and the immune system during viral infections.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — it may contain errors, so check the original before relying on it.
