Miguel Meira e Cruz, Masaaki Miyazawa, David Gozal
European Respiratory Journal 2020 55: 2001023; DOI: 10.1183/13993003.01023-2020
Circadian deregulation and poor or insufficient sleep may facilitate COVID-19 infection and severity https://bit.ly/2VUlIIJ
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiological agent of the pandemic coronavirus disease 2019 (COVID-19), is a newly found member of the Coronaviridae family, and is closely related to, albeit with important differences from, SARS-CoV. It enters human cells through the binding of surface spike (S) glycoprotein with angiotensin-converting enzyme 2 (ACE2). The distal S1 subunit of the S protein is responsible for receptor binding, while the transmembrane S2 subunit mediates fusion between the viral envelope and the target cell membrane following proteolytic cleavage by specific cellular enzymes such as transmembrane serine protease 2 for S protein priming. As it is likely that expression levels of ACE2 affect the efficiency of virus attachment and entry, as well as disease severity, and the interactions between viral S protein and ACE2 may directly cause lung injury, ACE2 may be a potential target of therapeutic and preventative interventions.
Viral infection pathophysiology and the role of the circadian clock system
The pathogenicity of viral infections can be affected by the host’s circadian clock system via two different mechanisms (figure 1): 1) direct regulation of viral replication within the target cells; and 2) indirect effects on innate and adaptive immune responses. For example, BMAL1, one of the key regulators of the circadian oscillator, directly affects mouse herpes virus infection in cultured cells and herpes virus replication is significantly enhanced in cells lacking the BMAL1 molecule. Conversely, acute infection with mouse herpes virus increases BMAL1 expression, which consequently deranges or enhances cell-autonomous rhythms depending at what point in the circadian cycle the infection takes place. Absence of BMAL1 affects the expression of cellular factors involved in protein biosynthesis, endoplasmic reticulum function and vesicular trafficking, all of which are important elements in intracellular replication of coronaviruses. Similarly, BMAL1 and REV-ERBα, the nuclear receptor family intracellular transcription factor required for synchronising and maintaining the peripheral clock, influence multiple steps in the hepatitis C virus life cycle, including its ability to enter hepatocytes as well as the RNA genome replication of the virus within hepatocytes. Knock-out approaches of Bmal1, genetic over-expression or increased REV-ERB activity using synthetic agonists, markedly reduce the replication of not only hepatitis C virus but also of other flaviviruses, such as Dengue and Zika viruses, through disruption of lipid signalling pathways.
Possible links between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the circadian clock system. Blue arrows indicate known links between cellular BMAL1 expression and replication of or responses to other viruses. Angiotensin-converting enzyme 2 (ACE2) expression on respiratory epithelial cells may be regulated through type 1 interferon (IFN-I)-induced mechanisms. As the surface S glycoprotein of SARS-CoV-2 binds the protease domain of ACE2, virus attachment may directly compete with the processing of angiotensin II (ATII) to Ang(1–7), a negative regulator of the renin–angiotensin system. ATII is known to be proinflammatory, while Ang(1–7) is anti-inflammatory. IFN-I signalling in the late phase of coronavirus infection induces exaggerated cytokine production and more severe lung injury. BMAL1 regulates IFN-I and chemokine CXCL5 production. ATII is known to affect the central clock system in the suprachiasmatic nuclei (SCN) through its effect on Per2 levels. TMPRSS2: transmembrane serine protease 2; ER: endoplasmic reticulum.
It is now well established that there is seasonal variation of BMAL1 expression, with the lowest values being recorded during winter, and these variations have been implicated in the high prevalence of respiratory viral diseases during winter, particularly in light of the observation that low BMAL1 expression enhances viral virulence. When mice were infected with herpes virus at various time-points of the day, significant effects were ascribed to the circadian clock . Thus, the circadian clock appears to influence both the infectivity of viruses as well as their ability to replicate inside the host. Furthermore, we surmise that since the circadian clock machinery is intrinsically involved in the regulation of angiotensin pathways, particularly in the transcriptional expression of ACE2, an imputed role for the circadian clock in regulating the infectivity to SARS-CoV-2 is highly probable.
The host circadian clock has now been recognised as a major modulator of immune/inflammatory responses in general, and in particular following respiratory virus infections in vivo. It has been shown that an endogenous circadian clock within lung epithelial cells modulates neutrophil recruitment through the chemokine ligand CXCL5. Genetic ablation of BMAL1 in the bronchioles resulted in a disruption of CXCL5 expression rhythms, leading to exaggerated inflammatory responses upon lipopolysaccharide stimulation. Depletion of BMAL1 also resulted in increased morbidity, mortality and virus replication in mice due to a lack of circadian regulation of interferon expression. Importantly, environmental disruption of circadian function by an experimental chronic jet lag model resulted in disrupted temporal expression of BMAL1 in the lungs and increased weight loss after respiratory Sendai virus infection.
The time of infection not only changes susceptibility but also predicts survival after influenza virus infection in mice. Mice infected at the beginning of their active phase showed higher mortality than those infected at the onset of the rest phase. These temporal differences were abolished in mice lacking BMAL1 expression. Interestingly, heightened inflammation was observed in mice infected at the onset of the active phase, while the number of natural killer (NK) cells was significantly higher in the group infected just prior to the rest phase, suggesting that circadian regulation of innate immunity plays a major role in these differences. Indeed, depletion of NK cells abolished the time of day differences, indicating that the molecular clock controls host cell responses to influenza virus infection via NK cell functions.