Fig. 3: The interconnected relationship between circadian rhythm, the immune system, and urinary tract function.

a Zeitgebers such as light, temperature and food synchronize the central clock in the suprachiasmatic nucleus (SCN), which in turn synchronizes all peripheral clocks present in the body. The clock comprises of interconnected transcriptional feedback loops, with heterodimers of the transcription factors brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles protein kaput (CLOCK) activating the expression of period (Per) and cryptochrome (Cry) genes. PER and CRY represent the negative arm of circadian control, whereby they form complexes to inhibit the activity of BMAL1–CLOCK and hence their own expression (loop 1). REV-ERBα/β and retinoid-related orphan receptor (ROR) α/β/γ alternatively regulate RORE promoter elements, which includes Bmal1 and Nfil3 (loop 2). NFIL3 and DBP can alternatively regulate-D-box promoter elements such as retinoid-related orphan receptor (ROR) α/β/γ (loop 3). All clock products from each of the loops can translocate back into the nucleus to either activate or repress these loops. b In mice, circadian rhythm influences susceptibility to various pathogens, cytokine secretion and immune cell trafficking. When mice transition into the active phase, the immune system is primed to respond to infection. In contrast, during the resting phase, immune functions are dampened and susceptibility to infections is increased. c Disrupted host circadian rhythm can interrupt both host immune system and urinary tract functions (i.e., increased voiding and impaired ability to concentrate urine). This is predicted to provide an environment that favors host colonization by UPEC. UPEC, in turn, may also reciprocally influence host circadian rhythms.