Elucidation of the mechanisms of proliferation/division, and metastasis of Sparganum proliferum and development of new treatment methods

• Project/Area Number: 20K07468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49040:Parasitology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Ishiwata Kenji 東京慈恵会医科大学, 医学部, 教授 (00241307)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Sparganum proliferum / Biology / Therapeutics development / experimental model / mitochondria / enzyme inhibitor / in vitro assay / mitochondrial enzyme / antibody / Experimental model / Proliferative assay / Anthelmintic drug assay / 芽殖孤虫 / 幼条虫の増殖と転移 / 抗寄生虫薬

Outline of Research at the Start

芽殖孤虫は、成虫が確認されていない幼条虫であり、これまで人体例は世界で21症例程であるが予後の極めて悪い寄生虫症を起こす。うち7例が本邦例で最新症例は1989年に虎ノ門病院から報告されている。患者の高い致死率は、骨を含む全身の臓器で幼条虫が無秩序に増殖・転移し、さらに既存の抗寄生虫薬が効かないことによる。申請者は、世界で唯一人体例から分離した芽殖孤虫をマウスで継代維持し、腹腔内で増殖し、肝臓、腹膜、横隔膜および肺に病変を形成することを確認している。本研究は、マウス感染系と培養系で芽殖孤虫の増殖および転移様式の一端を明らかにし、同時に新規治療法を開発することを目的としている。

Outline of Final Research Achievements

Sparganum proliferum multiplies and disseminates in the human body without limitation, and is fatal if detected late. There is no effective treatment for this parasitic disease, and it is extremely rare worldwide, however, the number of cases in Japan is relatively large.
Parasites maintained in the mouse abdominal cavity were periodically collected, and image analysis of these worms confirmed that they grew at a nearly constant rate. In this evaluation system, high concentrations of praziquantel and albendazole had no effect. Respiratory chain enzymes of the worm were active both aerobically and anaerobically and were inhibited at very low concentrations by the complex I inhibitor. The drug efficacy was observed in a dye exclusion test after co-cultivation. Ultrastructurally, changes were observed in the mitochondria, perinuclear and external parts of the worm body at 1 day of incubation, and these series of drug effects were more potent under aerobic conditions.

Academic Significance and Societal Importance of the Research Achievements

芽殖孤虫症は極めて稀な寄生虫症であるが、無制限な増殖と播種(転移)に加えて、既存の治療薬が効かないということが致死率を上げている要因である。幼虫形が無制限に増殖し転移する条虫は、他にもエキノコックス症を引き起こす多包条虫および単包条虫があるが両種は胚芽細胞の増殖による。個体レベルで成長し、個体数を増やす様式の理解は、生物学的に大変興味深く、得られる知見は寄生虫学を超えて細胞学および発生生物学などの発展のみならず医療への応用が期待される。一方で、芽殖孤虫に有効な治療薬の開発は同時に、有効な治療薬のないエキノコックス症への応用が多いに期待される。

Research Products

• [Journal Article] Genome of the fatal tapeworm Sparganum proliferum uncovers mechanisms for cryptic life cycle and aberrant larval proliferation (2021)
  • Author(s): Taisei Kikuchi, Mehmet Dayi, Vicky L. Hunt, Kenji Ishiwata, Atsushi Toyoda, Asuka Kounosu, Simo Sun, Yasunobu Maeda, Yoko Kondo, Belkisyole Alarcon de Noya, Oscar Noya, Somei Kojima, Toshiaki Kuramochi, Haruhiko Maruyama
  • Journal Title: Communications Biology Volume: N/A
  • Peer Reviewed / Open Access / Int'l Joint Research