Circadian metabolic adaptations to infections

Abstract

Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host-microbiota-pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Keywords: circadian clock; immune response; metabolism; microbiota; pathogen.

Figure 1.

Host–microbiota–pathogen metabolic cross-talks during infections. The circadian clock machinery is present within every cell of our body and controls metabolic and immune functions in homeostatic conditions, with the contribution of the gut microbiota. During infections, the host, the pathogen and the microbiota exploit circadian variations in metabolism to their own advantage and cooperate or compete to satisfy everyone’s need for nutrients at the right time of the day. Thus, the circadian regulation of specific metabolic pathways, such as glucose immunometabolism, the tryptophan catabolic pathway, iron availability and microbiota-derived short-chain fatty acids (SCFAs), could potentially shape immune responses against bacterial, viral, fungal or parasitic pathogens, likely influencing the balance between resistance and tolerance or the mutualistic-to-parasitic switch at a specific time of the day.

Figure 2.

IDO1-dependent day–night changes of the host response to Aspergillus fumigatus infection. Circadian IDO1 expression and activity drive day–night changes in the catabolism of the essential amino acid tryptophan through the kynurenine pathway. In the murine lung, low levels of kynurenine during the day contribute to improving the magnitude of the inflammatory response following infection with the opportunistic fungus A. fumigatus. At night, IDO1 increased activity may instead promote airway tolerance through Foxp3⁺ Treg thus causing hyphal infiltration of the lung and reduced fungal clearance. Created with BioRender.com.

Figure 3.

Circadian control of NAD⁺ biosynthetic pathways in the balance between tolerance and inflammation. The NAD+ salvage pathway, controlling the conversion of nicotinamide (NAM) to β-nicotinamide mononucleotide (NMN), is directly circadian-regulated through direct binding of the complex CLOCK-BMAL1-SIRT1 to E-boxes at the promoter of the Nampt gene, encoding for the rate-limiting enzyme of the pathway. During de novo synthesis, NAD⁺ is the final product of the kynurenine pathway, whose circadian oscillation is sustained by the rhythmic expression and activity of the enzyme IDO1. Both NAMPT and IDO1 are readily induced by infections or by inflammatory mediators in immune and epithelial cells. During infections, the switch from NAMPT-NAD⁺ axis, promoting a pro-inflammatory phenotype, to the kyn pathway, sustaining immune tolerance, may define the type of host immune response at a specific time of the day–night cycle. Created with BioRender.com.

Figure 4.

Diurnal competition for iron between the host, pathogen and microbiota. Iron is an essential nutrient for both host, pathogens and commensal microorganisms. In response to enteric pathogens, diurnal production by the inflamed intestine of lipocalin-2 (LCN2), an antimicrobial protein that prevents bacterial iron acquisition, favours the colonization of LCN2-resistant Salmonella over competing commensal microbes at a specific time of the day. Created with BioRender.com.