Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions

Abstract

Background: Circadian rhythm is characterised by daily variations in biological activity to align with the light and dark cycle. These diurnal variations, in turn, influence physiological functions such as blood pressure, temperature, and sleep-wake cycle. Though it is well established that the circadian pathway is linked to pro-inflammatory responses and circulating immune cells, its association with infectious diseases is widely unknown.

Objective: This comprehensive review aims to describe the association between circadian rhythm and host immune response to various kinds of infection.

Methods: We conducted a literature search in databases Pubmed/Medline and Science direct. Our paper includes a comprehensive analysis of findings from articles in English which was related to our hypothesis.

Findings: Molecular clocks determine circadian rhythm disruption in response to infection, influencing the host's response toward infection. Moreover, there is a complex interplay with intrinsic oscillators of pathogens and the influence of specific infectious processes on the CLOCK: BMAL1 pathway. Such mechanisms vary for bacterial and viral infections, both well studied in the literature. However, less is known about the association of parasitic infections and fungal pathogens with circadian rhythm modulation.

Conclusion: It is shown that bidirectional relationships exist between circadian rhythm disruption and infectious process, which contains interplay between the host's and pathogens' circadian oscillator, immune response, and the influence of specific infectious. Further studies exploring the modulations of circadian rhythm and immunity can offer novel explanations of different susceptibilities to infection and can lead to therapeutic avenues in circadian immune modulation of infectious diseases.

Keywords: Chrono-immunology; Circadian rhythm; Immune response; Infectious diseases; Inflammation; Melatonin; Molecular clocks.

Fig. 1

Schematic representation of the influence of Central and Peripheral Clocks on BMAL1-CLOCK Pathway and Immune Response. (Created with biorender.com by HH). SCN suprachiasmatic nucleus, BMAL-1 brain and muscle ARNT-like 1, CLOCK circadian locomotor output cycles kaput, CCGs clock controlled genes, PER period circadian regulator, CRY cryptochrome circadian regulator, Rev-Erb reverse orientation c-ErbA gene α, ROR retinoic acid-related orphan receptor, RRE rev response element, ACTH adrenocorticotropic hormone, NK cell natural killer cell, APC antigen-presenting cell, CCL2 C–C motif chemokine ligand 2, TNF tumour necrosis factor, IL-6 interleukin-6, IL-12 interleukin-12

Fig. 2

A summary of the association between viral infection and the CLOCK:BMAL1 pathway. (Created with biorender.com by HH). SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, BMAL-1 brain and muscle ARNT-like 1, CLOCK circadian locomotor output cycles kaput, CCGs clock controlled genes, PER period circadian regulator, CRY cryptochrome circadian regulator, Rev-Erb reverse orientation c-erbA gene α, ROR retinoic acid-related orphan receptor, RRE rev response element, SCD stearoyl-CoA-desaturase

Fig. 3

Sites for therapeutic intervention to modulate Rev-Erb and ROR expression in the suprachiasmatic nucleus (SCN) of the hypothalamus and the role of melatonin agonists on the CLOCK:BMAL1 pathway. (Created with biorender.com by HH). BMAL-1 brain and Muscle ARNT-like 1, CLOCK circadian locomotor output cycles kaput, CCGs clock controlled genes, Rev-Erb reverse orientation c-erbA gene α, ROR retinoic acid-related orphan receptor, RRE rev response element, SCD stearoyl-CoA-desaturase, c-Myc cellular Myc; MT 1/2, melatonin receptors, HCV hepatitis C virus, HIV human immunodeficiency virus