The circadian regulator BMAL1 programmes responses to parasitic worm infection via a dendritic cell clock

• Published in: Scientific reports Vol. 8; no. 1; pp. 3782 - 13
• Main Authors: Hopwood, Thomas W., Hall, Sarah, Begley, Nicola, Forman, Ruth, Brown, Sheila, Vonslow, Ryan, Saer, Ben, Little, Matthew C., Murphy, Emma A., Hurst, Rebecca J., Ray, David W., MacDonald, Andrew S., Brass, Andy, Bechtold, David A., Gibbs, Julie E., Loudon, Andrew S., Else, Kathryn J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2018; Nature Publishing Group
• Subjects: 13; 13/106; 13/21; 13/31; 13/51; 45; 45/91; 631/250/21/1293; 631/250/255/1715; 64; 64/110; 64/60; Animals; Antigens; ARNTL Transcription Factors - physiology; BMAL1 protein; Cells, Cultured; Circadian Rhythm; Circadian rhythms; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - parasitology; Feeding; Helper cells; Humanities and Social Sciences; Immunoglobulin G; Infections; Interleukin 12; Intestine; Lymph Nodes - immunology; Lymph Nodes - parasitology; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Science; Science (multidisciplinary); T-Lymphocytes - immunology; T-Lymphocytes - parasitology; Th2 Cells - immunology; Th2 Cells - parasitology; Trichuriasis - immunology; Trichuriasis - parasitology; Trichuris - pathogenicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-22021-5

Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (T H 2) 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 T H 2 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 T H 1/T H 2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.