Abstract
Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.
Highlights
Parasitic helminthic infection afflicts approximately one third of the world’s population, with the bulk of infection occurring within the gastrointestinal tract[1]
We show that antigen-presenting dendritic cells (DCs) are key components; with disruption of time-of-day responses observed in mice with a DC-conditional knock-out of the circadian regulating Bmal[1] gene
T. muris expulsion kinetics depends on time-of-day of infection
Summary
Parasitic helminthic infection afflicts approximately one third of the world’s population, with the bulk of infection occurring within the gastrointestinal tract[1]. Trichuris muris (T. muris) is a caecal dwelling parasitic helminth of mice Expulsion of this parasite has been rigorously characterised and critically requires a dominant TH2 immune response. In the context of intracellular protozoan parasite infection, circadian regulation of the magnitude of Leishmania infection has recently been described with an underpinning mechanism, thought to involve circadian control of chemokine expression by macrophages and rhythmic infiltration of neutrophils and macrophages to the site of infection[31]. It is not known whether the circadian clock plays a role in immunity to large, extracellular, multicellular parasites such as gastrointestinal helminths. Our data reveal that a DC circadian clock regulates efficient expulsion of the parasitic nematode T. muris
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