Fig 1.
Circadian regulation of the body.
Circadian rhythms impact diverse physiological processes across the body. The central clock in the brain integrates external and internal signals and communicates with tissue clocks to regulate organ functions. These include the nervous and endocrine system [4], cardiovascular system [1], respiratory tract [95], digestive system [61], reproductive [119] and urinary system [128], muscle skeletal system [2], and skin [111].
Fig 2.
Molecular clock and circadian criteria.
(A) Every cell in the body has an intrinsic circadian clock, in which transcriptional/translational feedback loops coordinate rhythmic gene expression. The activators BMAL1:CLOCK bind to E-boxes in promoter regions of genes and activate the expression of REV-ERB, ROR, PER, and CRY. PER:CRY inhibit BMAL1 activity, and ROR and REV-ERB compete for binding to RORE’s, including in the Bmal1 promoter. The figure represents 2 out of the 3 interconnected loops that regulate the clock, focusing on those that have been connected to host–pathogens interactions. (B) Criteria for biological rhythms to classify as circadian rhythms: (1) endogenous free-running period of approximately 24 hours; (2) entrainment to cues called Zeitgebers, for instance, light pulse causing phase shift; and (3) temperature compensation.
Fig 3.
Pathogens are influenced by the host’s microenvironments.
Bacteria, parasites, viruses, and fungi have evolved to maximize their colonization, replication, and transmission in specific niches within hosts. Multiple factors can vary depending on the infected organ. These include nutrient availability, variations in oxygen levels, endocrine regulation, and the presence of tissue-resident cells. The circadian clock can influence all these elements.
Fig 4.
Interplay between body clocks and pathogens.
Different pathogens target specific organs for replication, and some are capable of infecting multiple organs at various life stages. An interplay with circadian rhythms has been demonstrated for the pathogens shown. Liver: hepatitis B virus [44,45,51], hepatitis C virus [46,48, 50]. Blood: dengue virus [46], HIV [74–77], Leishmania [78], Plasmodium [86–90], Trypanosoma [91,92]. Respiratory tract: Aspergillus fumigatus [109,110], influenza virus [31,97–100], respiratory syncytial virus [104], SARS-CoV-2 [101–103], Sendai virus [98], Streptococcus pneumoniae [107,108]. Reproductive and urinary system: Candida albicans [129], Chlamydia muridarum [124–126]. Gastrointestinal tract: Citobacter rodentium [71], Clostridium difficile [70], Helicobacter pylori [31], Klebsiella aerogenes [65], Listeria monocytogenes [72], microbiome [53,62,67], Salmonella [68,69], Trichuris muris [73]. Skin: herpes virus [97,115–117], Staphylococcus aureus [114]. Brain: herpes virus [131], vesicular stomatitis virus [135], Zika virus [46], Trypanosoma [133].