Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis

Abstract

Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERBα mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERBα may mediate the circadian effect on survival following VSV infection. Blocking REV-ERBα activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERBα-mediated inhibition of CCL2 expression during viral-induced encephalitis may have a protective effect.circadian | inflammation | immune response | monocytes | vesicular stomatitis virus

Circadian control of lung inflammation in influenza infection

“…The second possibility is that the augmented balance between NK cells and Ly6C hi monocytes in the ZT23 group may favor a milieu conducive to efficient viral clearance and a well-contained state of inflammation. Our results are consistent with other reports where monocytes have been shown to induce excessive inflammation by different agents (Listeria and VSV) in other organs (3,10). In one model, the core clock gene Bmal1 induced Ccl2(3) while in another Rev-erbα suppressed Ccl2 (10,37).…”

“…Although the role of circadian regulation in systemic viral infections (8) has been described using Murid herpes virus (MHV) (9) and Vesicular Stomatis Virus (VSV) (10), its purview for respiratory viruses is limited (11). Some in vitro work (9) and results of a cluster-randomized study testing the efficacy of influenza vaccine in older adults (12) have suggested a role for circadian rhythms in influenza A infection.…”

BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes

“…16 focused on the ability of H3N1 IAV to disrupt normal clock gene expression patterns in mouse lung and proposed this event synergizes with cigarette smoke to promote chronic obstructive pulmonary disease (COPD). Finally, while this manuscript was in preparation and under review, several groups reported a role for circadian regulation in IAV, HSV, VSV and RSV infection 15, 38, 39 . Considered along with our results in SeV infection, it would appear that circadian clock function, and bmal1 in particular, is generally important for antiviral defense.…”

Immunometabolism: Is it under the eye of the clock?

“…THP-1 cells treated with GSK4112 prior to LPS, decreased a range of pro-inflammatory cytokines and chemokines, including Ccl2. Interestingly, the repression of Ccl2 by REV-ERB␣ is important in the onset, progression and resolution of vesicular stomatitis virus (VSV)-induced encephalitis [125]. Mice infected at ZT0 with VSV had a significant decrease in survival rate versus those infected at ZT12.…”