Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

An estimated 10% of the genome is under circadian control, which is regulated by light patterns. Food intake is another powerful cue. The circadian clock is an important gatekeeper for reducing immunity-associated costs and for increasing overall fitness, as mediated by external cues and internal oscillators of immune cells. Nearly all branches of innate and adaptive immune response show circadian oscillations. 117-119 CLOCK:BMAL1 activates transcription by binding to E-boxes of PER, CRY and REV-ERB which after a delay enter the nucleus and repress CLOCK:BMAL1 activity (and as such their own transcription). RORα activates transcription of Bmal1 by competing for the same binding sites as repressor REV-ERBα, β. A third loop includes transcriptional activator DBP and repressor NFIL3 that regulate expression of D-box-controlled genes such as PER. Ultimately these transcriptional oscillations in key regulators lead to circadian cues for cellular process over 24h cycles. Peripheral clocks are orchestrated by central clock and use essentially the same components, in virtually all cells. Some diseases show circadian timing (e.g. in RA, symptoms are exacerbated in early morning, which correlates with high TNF and IL-6 serum levels) and to address this matter, chronopharmacology aims at optimizing drug administration for peak efficacy and minimal side effects. [117] [118] [119] For gaining a better understanding of circadian regulation of global gene expression, Zhang et al. 120 used transcriptomics of 12 organs from mice (adrenal gland, aorta, brainstem, brown fat, cerebellum, heart, hypothalamus, kidney, liver, lung, skeletal muscle, and white fat) to analyse circadian gene expression by microarray and RNAseq. They found that 43% of protein-coding genes oscillated in at least one organ (only 10 transcripts oscillated in all, which included core clock genes). The authors also noted a 'rush hour' for transcription of circadian genes at times preceding dawn and dusk and that circadian genes cluster physically within the genome. Importantly, many gene products physically modulated by drugs show circadian patterns (119 of WHO's essential medicines modulate circadian genes; these include 56 of US's top 100 selling drugs, nearly half of which have half-lives < 6h). These findings emphasize the importance of dosing at appropriate times while decreasing side effects to a minimum. 120 Circadian regulation of gene expression was also noted in mice intestine, including for pattern-recognition receptors TLR2, −3, 4, − 5, 9. 121 Circadian rhythms influence critical components of innate and adaptive immunity. An example of this is TLR9, a pattern-recognition receptor for bacterial and viral DNA CpG. Following mice vaccination with ovalbumin adjuvanted with CpG at times of higher TLR9 expression, the adaptive response is stronger. Also disease severity in a sepsis mouse model correlated with TLR9 levels. 122 Circadian rhythms also affect viral replication. For instance, Edgar et al. 123 addressed the effect of circadian rhythms in herpes and influenza virus using murine strains to infect WT and Bmal1 KO mice and cell lines. WT mice infected with recombinant murid herpesvirus 4 (MuHV-4) at onset of resting phase had 10-fold greater replication than those infected before active phase. In contrast Bmal1 KO showed high levels of viral replication at any time. Similar data were obtained using herpes simplex virus 1, indicating that the effect was not strain-specifi