Development of new treatment against invasive fungal infection by S-nitrosated protein

• Project/Area Number: 15K15383
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Kinjo Yuki 国立感染症研究所, 真菌部, 室長 (20570831)
• Co-Investigator(Kenkyū-buntansha): 丸山 徹 熊本大学, 薬学部, 教授 (90423657)
• Co-Investigator(Renkei-kenkyūsha): ISHIMA YU 徳島大学, 大学院医歯薬学研究部, 准教授 (00457590) ; UENO KEIGO 国立感染症研究所, 真菌部第三室, 主任研究官 (10550220)
• Research Collaborator: SAKAI JUN 国立感染症研究所, 真菌部第三室, 協力研究員 ; SAITOH NORIKO 国立感染症研究所, 電顕室, 職員 ; TAKATSUKA SHOGO 国立感染症研究所, 真菌部第三室, 研究員 ; ABE MASAHIRO 国立感染症研究所, 真菌部第三室, 協力研究員 ; NAKAHARA MAKIKO 国立感染症研究所, 真菌部第三室, 研究生 ; KAWAKUBO SHUN 国立感染症研究所, 真菌部第三室, 実習生
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 感染症 / 真菌 / 抗真菌薬 / S-ニトロソ化蛋白 / 内科 / 薬学

Outline of Final Research Achievements

Invasive fungal infections are associated with high mortality rates. The emergence of drug-resistant fungi is a great concern because of the limited number of antifungal drugs. In this study, we tested antifungal activities of S-nitrosated protein that had been developed as a stable donor of nitric oxide against major fungal pathogens including Candida spp., Cryptococcus spp. and Aspergillus fumigatus. S-nitrosated protein inhibited the growth of these fungi including drug-resistant strains. S-nitrosated protein increased the production of reactive oxygen species and decreased the mitochondrial membrane potential in C. albicans, indicating cell death of this fungus. Furthermore, scanning electron microscopy showed morphological changes in C. albicans upon treatment with this protein. These results demonstrate that S-nitrosated protein has antifungal activities against major fungal pathogens, indicating that this protein is a potential candidate for a new class of antifungal drugs.

Research Products

• [Journal Article] Evasion of Innate Immune Responses by the Highly Virulent Cryptococcus gattii by Altering Capsule Glucuronoxylomannan Structure (2016)
  • Author(s): Urai M, Kaneko Y, Ueno K, Okubo Y, Aizawa T, Fukazawa H, Sugita T, Ohno H, Shibuya K, Kinjo Y and Miyazaki Y
  • Journal Title: Front Cell Infect Microbiol Volume: 5 Pages: 101-101
  • DOI: 10.3389/fcimb.2015.00101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dendritic Cell-Based Vaccine Against Fungal Infection (2016)
  • Author(s): Ueno K, Urai M, Ohkouchi K, Miyazaki Y, Kinjo Y.
  • Journal Title: Methods Mol Biol Volume: 1403 Pages: 537-4
  • DOI: 10.1007/978-1-4939-3387-7_30
  • ISBN: 9781493933853, 9781493933877
• [Journal Article] 侵襲性カンジダ感染症の発症,炎症反応および薬剤耐性に関する基盤的研究 (2015)
  • Author(s): 金城 雄樹, 田辺 公一, 上野 圭吾, 北野 尚樹, 名木 稔, 浦井 誠, 星野 泰隆, 梅山 隆, 山越 智, 宮﨑 義継
  • Journal Title: 化学療法の領域 Volume: 31 Pages: 113-119
• [Journal Article] クリプトコックス症の概要 (2015)
  • Author(s): 金城 雄樹，梅山 隆，宮﨑 義継，金子 幸弘
  • Journal Title: IASR Volume: 36 Pages: 185-186
• [Journal Article] Interferon-γ promotes phagocytosis of Cryptococcus neoformans but not Cryptococcus gattii by murine macrophages (2015)
  • Author(s): Ikeda-Dantsuji Y, Ohno H, Tanabe K, Umeyama T, Ueno K, Nagi M, Yamagoe S, Kinjo Y, Miyazaki Y
  • Journal Title: J Infect Chemother Volume: 21 Issue: 12 Pages: 831-836
  • DOI: 10.1016/j.jiac.2015.08.001
  • Peer Reviewed / Int'l Joint Research