Host lipids that regulate the function of replication factories of RNA viruses

• Project/Area Number: 17H05070
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Virology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: YAMANE Daisuke 公益財団法人東京都医学総合研究所, 疾患制御研究分野, 主席研究員 (60782761)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000); Fiscal Year 2019: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2018: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: ウイルス / 感染症 / 脂質 / RNAウイルス / 複製複合体 / 脂質代謝 / 脂肪酸 / 小胞体膜 / 宿主因子

Outline of Final Research Achievements

Positive strand RNA viruses initiate genome replication within specialized membrane vesicles, designated "replication factory", in infected cells. Such organelles are typically induced by engagement of viral proteins and associated with morphological changes in the structure of host internal membranes. Whereas the process involved in formation of the replication factory must involve alterations in host lipid metabolism, the mechanistic details remain poorly characterized. Through investigations by means of microarray analysis, comprehensive lipidomics analysis and fatty acid profiling, this study has revealed that RNA viruses modulate cellular lipid profiles via modulation of cellular phospholipase activity that cleaves fatty acid tails from membrane phospholipids as well as fatty acid desaturases. Importantly, analyses of fatty acid metabolic pathways that catalyze fatty acid cleavage or desaturation identified host targets that could lead to development of virus-specific antivirals.

Academic Significance and Societal Importance of the Research Achievements

ウイルス感染特異的に変化する脂質代謝を理解することはウイルスの感染・複製機構の解明のみならず、その代謝経路を標的とすることでウイルス特異的に作用する創薬に繋がる。この研究において、異なるウイルス感染によって普遍的および特異的に誘導される脂質代謝変化を包括的に捉えたことにより、脂肪酸代謝の重要性を見出すことに繋がった。また、脂肪酸代謝を標的とする薬剤がウイルス複製を有意に変化させることを見出したことから、脂肪酸代謝酵素が抗ウイルス薬の標的分子となり得ることを実証できた。この研究から得られた成果をもとに、今後動物感染モデルを用いた試験を通じて、より安全性の高い創薬開発へと発展することが期待できる。

Research Products

• [Int'l Joint Research] The University of North Carolina(米国)
• [Journal Article] Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses (2021)
  • Author(s): Feng Hui、Zhang Yi-Bing、Gui Jian-Fang、Lemon Stanley M.、Yamane Daisuke
  • Journal Title: PLOS Pathogens Volume: 17 Issue: 1 Pages: e1009220-e1009220
  • DOI: 10.1371/journal.ppat.1009220
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors (2020)
  • Author(s): Dultz Georg、Shimakami Tetsuro、Schneider Markus、Murai Kazuhisa、Yamane Daisuke、Marion Antoine、Zeitler Tobias M.、Stross Claudia、Grimm Christian、Richter Rebecca M.、B?umer Katrin、Yi MinKyung、Biondi Ricardo M.、Zeuzem Stefan、Tamp? Robert、Antes Iris、Lange Christian M.、Welsch Christoph
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 40 Pages: 13862-13874
  • DOI: 10.1074/jbc.ra120.013898
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses (2019)
  • Author(s): Yamane D, Feng H, Rivera-Serrano EE, Selitsky SR, Hirai-Yuki A, Das A, McKnight KL, Misumi I, Hensley L, Lovell W, González-López O, Suzuki R, Matsuda M, Nakanishi H, Ohto-Nakanishi T, Hishiki T, Wauthier E, Oikawa T, Morita K, Reid LM, Sethupathy P, Kohara M, Whitmire JK, Lemon SM
  • Journal Title: Nature Microbiology Volume: 印刷中 Issue: 7 Pages: 1096-1104
  • DOI: 10.1038/s41564-019-0425-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatovirus 3ABC proteases and evolution of mitochondrial antiviral signaling protein (MAVS) (2019)
  • Author(s): Feng Hui、Sander Anna-Lena、Moreira-Soto Andr?s、Yamane Daisuke、Felix Drexler Jan、Lemon Stanley M.
  • Journal Title: Journal of Hepatology Volume: in press Issue: 1 Pages: 25-34
  • DOI: 10.1016/j.jhep.2019.02.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stearoyl-CoA desaturase-1 is required for flavivirus RNA replication (2019)
  • Author(s): Hishiki Takayuki、Kato Fumihiro、Nio Yasunori、Watanabe Satoru、Wen Tan Nicole Wei、Yamane Daisuke、Miyazaki Yasuyuki、Lin Chun-Chieh、Suzuki Rieko、Tajima Shigeru、Lim Chang-Kweng、Saijo Masayuki、Hijikata Makoto、Vasudevan Subhash G.、Takasaki Tomohiko
  • Journal Title: Antiviral Research Volume: 165 Pages: 42-46
  • DOI: 10.1016/j.antiviral.2019.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains. (2017)
  • Author(s): Benzine T, Brandt R, Lovell WC, Yamane D, Neddermann P, De Francesco R, Lemon SM, Perelson AS, Ke R, McGivern DR.
  • Journal Title: PLoS Pathog. Volume: 13 Issue: 6 Pages: e1006343-e1006343
  • DOI: 10.1371/journal.ppat.1006343
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NLRX1 promotes immediate IRF1-directed antiviral responses by limiting dsRNA-activated translational inhibition mediated by PKR. (2017)
  • Author(s): Feng H, Lenarcic EM, Yamane D, Wauthier E, Mo J, Guo H, McGivern DR, Gonzalez-Lopez O, Misumi I, Reid LM, Whitmire JK, Ting JP, Duncan JA, Moorman NJ, Lemon SM.
  • Journal Title: Nat Immunol. Volume: 18 Issue: 12 Pages: 1299-1309
  • DOI: 10.1038/ni.3853
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脂溶性ビタミンを介した肝炎ウイルス複製制御機構 (2020)
  • Author(s): 山根大典
  • Organizer: 第364回脂溶性ビタミン総合研究委員会
  • Invited
• [Presentation] 肝細胞に内在するRNA ウイルス抑制シグナルとその制御機構 (2020)
  • Author(s): 山根大典
  • Organizer: 第65回肝炎ウイルスセミナー
  • Invited
• [Presentation] RARRES3 mediates interferon regulatory factor 1-induced suppression of hepatitis A virus replication through modulation of the mTOR activity. (2019)
  • Author(s): Daisuke Yamane, Asuka Hirai-Yuki, Michinori Kohara, Stanley M. Lemon
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] MAVS-independent activity of interferon regulatory factor 1 restricts hepatotropic RNA virus infections (2018)
  • Author(s): Daisuke Yamane, Asuka Hirai-Yuki, Ichiro Misumi, Michinori Kohara, Jason K Whitmire, and Stanley M Lemon
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Efficient replication of non-adapted hepatitis C virus isolates in cell culture (2017)
  • Author(s): Daisuke Yamane, Michinori Kohara
  • Organizer: 第65回日本ウイルス学会学術集会
• [Remarks] ウイルス感染を抑制する新たな肝細胞の自然免疫の仕組みを発見
  • URL: http://www.igakuken.or.jp/topics/2019/0415.html
• [Remarks] How Liver Cells Protect Against Viral Attacks
  • URL: https://globalhealth.unc.edu/2019/04/researchers-identify-liver-cells-protect-viral-attacks/