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PLoS Genet. 2016 Jan 4;12(1):e1005773. doi: 10.1371/journal.pgen.1005773. eCollection 2016 Jan.

TrpA1 Regulates Defecation of Food-Borne Pathogens under the Control of the Duox Pathway.

Du EJ1,2, Ahn TJ1,2, Kwon I1,2, Lee JH1,2, Park JH3, Park SH1,4, Kang TM1,4, Cho H1,4, Kim TJ1,5, Kim HW6, Jun Y7, Lee HJ8, Lee YS9, Kwon JY3, Kang K1,2.

Author information

1
Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
2
Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
3
Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
4
Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea.
5
Department of Immunobiology, Sungkyunkwan University School of Medicine, Suwon, Korea.
6
College of Life Sciences, Sejong University, Seoul, Korea.
7
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
8
Kangwon National University College of Medicine, Chuncheon, Korea.
9
College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.

Abstract

Pathogen expulsion from the gut is an important defense strategy against infection, but little is known about how interaction between the intestinal microbiome and host immunity modulates defecation. In Drosophila melanogaster, dual oxidase (Duox) kills pathogenic microbes by generating the microbicidal reactive oxygen species (ROS), hypochlorous acid (HOCl) in response to bacterially excreted uracil. The physiological function of enzymatically generated HOCl in the gut is, however, unknown aside from its anti-microbial activity. Drosophila TRPA1 is an evolutionarily conserved receptor for reactive chemicals like HOCl, but a role for this molecule in mediating responses to gut microbial content has not been described. Here we identify a molecular mechanism through which bacteria-produced uracil facilitates pathogen-clearing defecation. Ingestion of uracil increases defecation frequency, requiring the Duox pathway and TrpA1. The TrpA1(A) transcript spliced with exon10b (TrpA1(A)10b) that is present in a subset of midgut enteroendocrine cells (EECs) is critical for uracil-dependent defecation. TRPA1(A)10b heterologously expressed in Xenopus oocytes is an excellent HOCl receptor characterized with elevated sensitivity and fast activation kinetics of macroscopic HOCl-evoked currents compared to those of the alternative TRPA1(A)10a isoform. Consistent with TrpA1's role in defecation, uracil-excreting Erwinia carotovora showed higher persistence in TrpA1-deficient guts. Taken together, our results propose that the uracil/Duox pathway promotes bacteria expulsion from the gut through the HOCl-sensitive receptor, TRPA1(A)10b, thereby minimizing the chances that bacteria adapt to survive host defense systems.

PMID:
26726767
PMCID:
PMC4699737
DOI:
10.1371/journal.pgen.1005773
[Indexed for MEDLINE]
Free PMC Article

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