The Circadian Clock and Viral Infections

Abstract

The circadian clock controls several aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. Our circadian rhythms are driven by an endogenous central clock in the brain that synchronizes with clocks in peripheral tissues, thereby regulating our immune system and the severity of infections. These rhythms affect the pharmacokinetics and efficacy of therapeutic agents and vaccines. The core circadian regulatory circuits and clock-regulated host pathways provide fertile ground to identify novel antiviral therapies. An increased understanding of the role circadian systems play in regulating virus infection and the host response to the virus will inform our clinical management of these diseases. This review provides an overview of the experimental and clinical evidence reporting on the interplay between the circadian clock and viral infections, highlighting the importance of virus-clock research.

Keywords: COVID-19; circadian rhythm; virology; virus-clock; viruses.

Figure 1.

Circadian regulation of the human body. External signals entrain the body’s central clock, the SCN in the brain, which in turn synchronizes peripheral clocks in organs and results in the molecular regulation of each cellular clock. Transcriptional/translational feedback loops coordinate rhythmic gene expression, and proteasomal degradation of the components restarts the system. BMAL1:CLOCK binds to E-Boxes and activates the expression of REV-ERB, RORα, and PER:CRY, which then directly inhibit BMAL1:CLOCK or act on Bmal1 promoter activity. SCN = suprachiasmatic nucleus; BMAL = brain and muscle ARNT-like 1; CLOCK = circadian locomotor output cycles kaput; ROR = related orphan receptor; PER = Period; CRY = Cryptochrome. Created with BioRender.com

Figure 2.

Virus structure, life cycle, and disease outcome. Viruses bear their genetic information as encapsidated RNA or DNA that may be enclosed in a lipid envelope. After the virus entry into the host cell, the genetic material is released, translated, and replicated. For some viruses, their genetic material is imported and replicated in the nucleus. After translation of the viral proteins and replication of the genome, new viral particles are assembled and released to complete the life cycle. Virus infection can be resolved by host immune responses or persist and cause chronic disease. Created with BioRender.com

Figure 3.

Cellular clock affects the virus life cycle. The cellular clock can influence viral infection at multiple steps in the virus life cycle, from the regulation of entry receptors to lipid-dependent pathways for particle genesis. In addition, immune responses combating viral infections, such as nucleic acid sensing and the activity of immune cells, are regulated by cellular circadian clocks. Created with BioRender.com