For Whom the Clock Ticks: Clinical Chronobiology for Infectious Diseases

Abstract

The host defense against pathogens varies among individuals. Among the factors influencing host response, those associated with circadian disruptions are emerging. These latter depend on molecular clocks, which control the two partners of host defense: microbes and immune system. There is some evidence that infections are closely related to circadian rhythms in terms of susceptibility, clinical presentation and severity. In this review, we overview what is known about circadian rhythms in infectious diseases and update the knowledge about circadian rhythms in immune system, pathogens and vectors. This heuristic approach opens a new fascinating field of time-based personalized treatment of infected patients.

Keywords: circadian rhythm; clock genes; immune response; infectious diseases; microbiota; microorganisms.

Figure 1

Circadian rhythm of the immune system components. The suprachiasmatic nucleus is the central oscillator that mediates all circadian variations in humans. It receives synchronization information with the day/night cycle via its retinal connection and then sends projections to other regions of the brain with local clocks such as immune organs (lymph nodes, spleen, thymus, and bone marrow) and activates peripheral clocks (activation of circadian feedback loops). In most immune cells (represented by functions such as phagocytosis and cytokine production), the feedback loops function as follows: once its gene is expressed, the BMAL1 protein dimerizes with CLOCK in the nucleus; the CLOCK/BMAL1 heterodimer binds to the E-box promoter sequences and induces expression of Pers, Crys, Reverbs, Rors, and Ccgs. The PERs and CRYs proteins dimerize in the presence of the casein kinase 1 (Ck1), then return to the nucleus to prevent the binding of the dimer CLOCK/BMAL1 on DNA. PERs proteins are phosphorylated by Ck1 and then degraded by the proteasome. REVERBS and RORs have antagonistic effects on Bmal1 expression: they bind the promoter of its gene and then induce (RORs) or inhibit (REVERBs) its expression. DBP protein induces the expression of Pers and Ccgs by binding D-box promoter sequences; it is inhibited by NFIL3. Positive and negative factors are represented by red and green arrows, respectively.

Figure 2

Circadian rhythm in cyanobacteria. The KaiC protein (red diamond) has two loop domains (CI and CII) and serine (S) and threonine (T) phosphorylation sites. At dawn, the increase in the ADP/ATP ratio, which reaches its maximum at noon, leads to the fixation of KaiA (yellow rectangle) on the CII domain, the phosphorylation of the T site and the induction of a training signal of photosynthesis elements. At nightfall, the increase in oxidized quinones following the initiation of the nitrogen cycle leads to the phosphorylation of the S site; KaiC is doubly phosphorylated. SasA (blue rectangle) is then fixed on the CI domain and activates the transcription factor RepA, which in turn induces expression of the target genes involved in the clock loop or others functions such as their multiplication. Finally, KaiB (green rectangle) releases KaiA and SasA, disable RepA via its interaction with the repressor CikA, and end up dephosphorylating KaiC which first finds itself serine phosphorylated.