The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction

Abstract

Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenance of life and that characterize the execution of activities of daily life generally present periodic variations, which are mostly synchronized with the light-dark cycle determined by Earth's rotation on its axis. These rhythms with 24-h periodicity, defined as circadian, influence events linked to the interaction between hosts and hosted microorganisms and can dramatically determine the outcome of this interplay. As for the various pathological conditions resulting from host-microorganism interactions, a particularly interesting scenario concerns infections by viruses. When a viral agent enters the body, it alters the biological processes of the infected cells in order to favour its replication and to spread to various tissues. Though our knowledge concerning the mutual influence between the biological clock and viruses is still limited, recent studies start to unravel interesting aspects of the clock-virus molecular interplay. Three different aspects of this interplay are addressed in this mini-review and include the circadian regulation of both innate and adaptive immune systems, the impact of the biological clock on viral infection itself, and finally the putative perturbations that the virus may confer to the clock leading to its deregulation.

Keywords: circadian rhythms; clock; host; immune system; virus.

Figure 1

Schematic illustration of the interplay between the biological clock, virus replication, and the immune system at the cellular level: The components of the molecular clockwork are depicted within the cell, with green arrows indicating activation and red arrows indicating inhibition. The presence of viral genomes is indicated by squiggles. Below the cell are elements of the immune response. The orange arrows indicate interactions among virions, biological clocks, and immune competent cells. The interaction of virions and their nucleic acid core with these two players impacts viral replication and rhythmic patterns of host–hosted molecular trade off. The immune system with its innate and adaptive arms provides shielding against viral infections with a number of molecular factors and effectors, such as dendritic cells, T and B cells, macrophages, and natural killer cells. These are engaged to hold up and hinder virus replication and dissemination through the secretion of cytokines and the production of specific antibodies. The components and, ultimately, the complex function of the immune system are rhythmically driven by the biological clock and, in turn, influence the function of the molecular clockwork. Viral particles impact the interplay between immune and circadian systems.