Induction of a dormant form of Trypanosoma cruzi by concanavalin A

• Project/Area Number: 16K15268
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Parasitology (including sanitary zoology)
• Research Institution: Iwaki Meisei University (2017-2018); Juntendo University (2016)
• Principal Investigator: Nara Takeshi いわき明星大学, 薬学部, 教授 (40276473)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: クルーズトリパノソーマ / シャーガス病 / 休眠 / シスト形成 / トリパノソーマ / 分化誘導治療

Outline of Final Research Achievements

The flagellate protist, Trypanosoma cruzi, is a causative agent of Chagas disease. Here we demonstrate “a cyst-like form” of T. cruzi induced by treatment with concanavalin A (ConA). In the presence of ConA, the parasites became swollen along with enlargement of vacuole and the cellular organelles, like nuclei, mitochondria, and flagella, multiplied synchronously within the cyst wall. Finally, newly formed, motile organisms budded inside the cavity. Immunohistochemical and mass spectrometric analysis suggested the potential target of ConA is tubulin, a component of microtubule, and T. cruzi-specific cystein protease, cruzipain. Our data highlight its morphological flexibility of T. cruzi and provide hints on how the parasites persist in the course of chronic Chagas disease.

Academic Significance and Societal Importance of the Research Achievements

シャーガス病の治療において、急性期では著効を示すベンズニダゾールやニフルチモックスといった治療薬は慢性期では効果が低い。この事実は、急性期と慢性期でクルーズトリパノソーマの性質そのものが異なっていることを強く示唆し、抗結核薬が分裂休止菌に対しては効果がないことと極めて類似している。本研究によって、代謝活性および分裂能が著しく低下したクルーズトリパノソーマを誘導できることが明らかとなった。これは、シャーガス病の慢性期における病像を理解する上で極めて重要な発見である。

Research Products

• [Journal Article] Insights into the ubiquinol/dioxygen binding and proton relay pathways of the alternative oxidase (2019)
  • Author(s): Shiba Tomoo、Inaoka Daniel Ken、Takahashi Gen、Tsuge Chiaki、Kido Yasutoshi、Young Luke、Ueda Satoshi、Balogun Emmanuel Oluwadare、Nara Takeshi、Honma Teruki、Tanaka Akiko、Inoue Masayuki、Saimoto Hiroyuki、Harada Shigeharu、Moore Anthony L.、Kita Kiyoshi
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Bioenergetics Volume: 1860 Issue: 5 Pages: 375-382
  • DOI: 10.1016/j.bbabio.2019.03.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Perlecan, a heparan sulfate proteoglycan, regulates systemic metabolism with dynamic changes in adipose tissue and skeletal muscle (2018)
  • Author(s): Yamashita Y, Nakada S, Yoshihara T, Nara T, Furuya N, Miida T, Hattori N, Arikawa-Hirasawa E
  • Journal Title: Scientific Reports Volume: 8(1) Issue: 1 Pages: 7766-7766
  • DOI: 10.1038/s41598-018-25635-x
  • Peer Reviewed / Open Access
• [Journal Article] Design and Synthesis of Potent Substrate-based Inhibitors of the Trypanosoma cruzi Dihydroorotate Dehydrogenase (2017)
  • Author(s): D. K. Inaoka, M. Iida, S. Hashimoto, T. Tabuchi,T. Kuranaga, E. O. Balogun, T. Honma, A. Tanaka, S. Harada, T. Nara, K. Kita, M. Inoue
  • Journal Title: Bioorg. Med. Chem. Volume: 25 Issue: 4 Pages: 1465-1470
  • DOI: 10.1016/j.bmc.2017.01.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization and diagnostic application of Trypanosoma cruzi trypomastigote excreted-secreted antigens shed in exosomes released from infected mammalian cells. (2017)
  • Author(s): Bautista-Lopez N, Ndao M, Camargo F, Nara T, Jardim A, Annoura T, Hardie D, Borchers C.
  • Journal Title: J Clin Microbiol. 2017 55:744-758. Volume: 55 Issue: 3 Pages: 744-758
  • DOI: 10.1128/jcm.01649-16
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] シャーガス病：グローバル化・温暖化と感染症対策 (2017)
  • Author(s): 奈良武司
  • Journal Title: 小児科臨床． Volume: 70巻増刊号 Pages: 2267-2271
• [Journal Article] Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells. (2016)
  • Author(s): Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A,
  • Journal Title: Biochem Biophys Res Commun Volume: in press Issue: 1 Pages: 125-132
  • DOI: 10.1016/j.bbrc.2016.03.064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential remodelling of peroxisome function underpins the environmental and metabolic adaptability of diplonemids and kinetoplastids. (2016)
  • Author(s): Morales J, Hashimoto M, Williams TA, Hirawake-Mogi H, Makiuchi T, Tsubouchi A, Kaga N, Taka H, Fujimura T, Koike M, Mita T, Bringaud F, Concepcion JL, Hashimoto T, Embley TM, Nara T.
  • Journal Title: Proc R Soc B Volume: 283 Issue: 1830 Pages: 20160520-20160520
  • DOI: 10.1098/rspb.2016.0520
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Morpholino antisense oligo inhibits trans-splicing of pre-inositol 1,4,5-trisphosphate receptor mRNA of Trypanosoma cruzi and suppresses parasite growth and infectivity. (2016)
  • Author(s): Hashimoto M, Nara T, Mita T, Mikoshiba K.
  • Journal Title: Parasitol Int. Volume: 65 Issue: 3 Pages: 175-179
  • DOI: 10.1016/j.parint.2015.12.001
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Open Form Inducer Approach for Structure-Based Drug Design (2016)
  • Author(s): D. K. Inaoka, M. Iida, T. Tabuchi, T. Honma, N. Lee, S. Hashimoto, S. Matsuoka, T. Kuranaga, K. Sato, T. Shiba, K. Sakamoto, E. O. Balogun, S. Suzuki, T. Nara, J. R. Rocha, C. A. Montanari, A. Tanaka, M. Inoue, K. Kita, S. Harada
  • Journal Title: PLoS ONE Volume: 11 Issue: 11 Pages: e0167078-e0167078
  • DOI: 10.1371/journal.pone.0167078
  • NAID: 120006987593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dube syndrome. (2016)
  • Author(s): Hoshika Y, Takahashi F, Togo S, Hashimoto M, Nara T, Kobayashi T, Nurwidya F, Kataoka H, Kurihara M, Kobayashi E, Ebana H, Kikkawa M, Ando K, Nishino K, Hino O, Takahashi K, Seyama K.
  • Journal Title: Physiol Rep Volume: 4 Issue: 21
  • DOI: 10.14814/phy2.13025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inositol 1,4,5-trisphosphate receptor determines intracellular Ca2+ concentration in Trypanosoma cruzi throughout its life cycle (2016)
  • Author(s): Hashimoto M, Doi M, Kurebayashi N, Furukawa K, Hirawake-Mogi H, Ohmiya Y, Sakurai T, Mita T, Mikoshiba K, Nara T.
  • Journal Title: FEBS Open Bio. Volume: 6(12) Issue: 12 Pages: 1178-1185
  • DOI: 10.1002/2211-5463.12126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Book] ハリソン内科学第5版 (2017)
  • Author(s): 奈良武司監訳および訳、福井次矢、黒川清監修
  • Total Pages: 3132
  • Publisher: メディカル・サイエンス・インターナショナル
• [Patent(Industrial Property Rights)] トリパノソーマ関連疾患治療薬、トリパノソーマ原虫の感染阻止または殺虫方法、およびその利用 (2017)
  • Inventor(s): 奈良武司、御子柴克彦、橋本宗明
  • Industrial Property Rights Holder: 国立研究開発法人理化学研究所、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Acquisition Date: 2017