The ATP Transporter VNUT Mediates Induction of Dectin-1-Triggered Candida Nociception

Kenta Maruyama; Yasunori Takayama; Erika Sugisawa; Yu Yamanoi; Takashi Yokawa; Takeshi Kondo; Ken-Ichi Ishibashi; Bikash Ranjan Sahoo; Naoki Takemura; Yuki Mori; Hisashi Kanemaru; Yutaro Kumagai; Mikaël M Martino; Yoshichika Yoshioka; Hisao Nishijo; Hiroki Tanaka; Atsushi Sasaki; Naohito Ohno; Yoichiro Iwakura; Yoshinori Moriyama; Masatoshi Nomura; Shizuo Akira; Makoto Tominaga

doi:10.1016/j.isci.2018.08.007

The ATP Transporter VNUT Mediates Induction of Dectin-1-Triggered Candida Nociception

iScience. 2018 Aug 31:6:306-318. doi: 10.1016/j.isci.2018.08.007. Epub 2018 Aug 15.

Authors

Kenta Maruyama¹, Yasunori Takayama², Erika Sugisawa³, Yu Yamanoi⁴, Takashi Yokawa⁵, Takeshi Kondo³, Ken-Ichi Ishibashi⁶, Bikash Ranjan Sahoo³, Naoki Takemura⁷, Yuki Mori⁸, Hisashi Kanemaru³, Yutaro Kumagai⁹, Mikaël M Martino¹⁰, Yoshichika Yoshioka⁸, Hisao Nishijo¹¹, Hiroki Tanaka³, Atsushi Sasaki¹², Naohito Ohno⁶, Yoichiro Iwakura¹³, Yoshinori Moriyama¹⁴, Masatoshi Nomura¹⁵, Shizuo Akira³, Makoto Tominaga¹⁶

Affiliations

¹ Laboratory of Host Defense, Osaka University, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan. Electronic address: maruyama@biken.osaka-u.ac.jp.
² Thermal Biology group, Exploratory Research Center on Life and Living Systems National Institutes of Natural Sciences, Okazaki Aichi 444-8787, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, the Graduate University for Advanced Studies, Aichi 444-8787, Japan.
³ Laboratory of Host Defense, Osaka University, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.
⁴ Thermal Biology group, Exploratory Research Center on Life and Living Systems National Institutes of Natural Sciences, Okazaki Aichi 444-8787, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, the Graduate University for Advanced Studies, Aichi 444-8787, Japan; Research Laboratory, Ikedamohando Co., Ltd., 2-16-16 Iwamoto-cho, Chiyoda-ku, Tokyo 101-0032, Japan.
⁵ BioView Corporation, 2-16-16 Iwamoto-cho, Chiyoda-ku, Tokyo 101-0032, Japan.
⁶ Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
⁷ Department of Mucosal Immunology, School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan.
⁸ Laboratory of Biofunctional Imaging, Osaka University, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.
⁹ Laboratory of Host Defense, Osaka University, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan; Biotechnology Research Institute for Drug Discovery National Institute of Advanced Industrial Science and Technology Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.
¹⁰ Laboratory of Host Defense, Osaka University, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan; European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Innovation Walk, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
¹¹ System Emotional Science (Physiology), Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
¹² Research Unit/Neuroscience Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
¹³ Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
¹⁴ Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, Japan.
¹⁵ Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.
¹⁶ Thermal Biology group, Exploratory Research Center on Life and Living Systems National Institutes of Natural Sciences, Okazaki Aichi 444-8787, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, the Graduate University for Advanced Studies, Aichi 444-8787, Japan; Institute for Environmental and Gender Specific Medicine, Juntendo University, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan. Electronic address: tominaga@nips.ac.jp.

Abstract

Candida albicans infection can cause skin, vulvar, or oral pain. Despite the obvious algesic activity of C. albicans, the molecular mechanisms of fungal nociception remain largely unknown. Here we show that the C. albicans-specific signaling pathway led to severe mechanical allodynia. We discovered that C. albicans-derived β-glucan stimulated nociceptors depending on Dectin-1, and two pathways in inflammatory pain. The major pathway operates via the Dectin-1-mediated ATP-P2X₃/P2X_2/3 axis through intercellular relationships between keratinocytes and primary sensory neurons, which depends on the ATP transporter vesicular nucleotide transporter (VNUT). The other pathway operates via the Dectin-1-mediated PLC-TRPV1/TRPA1 axis in primary sensory neurons. Intriguingly, C. albicans-derived β-glucan has the ability to enhance histamine-independent pruritus, and VNUT inhibitor clodronate can be used to treat unpleasant feelings induced by β-glucan. Collectively, this is the first report to indicate that Dectin-1 and VNUT mediated innate sensory mechanisms that detect fungal infection.

Keywords: Medical Microbiology; Molecular Mechanism of Behavior; Molecular Neuroscience.