Development of therapeutic strategies for atovaquone-resistant Babesia microti that infects human

• Project/Area Number: 18F18399
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 外国
• Review Section: Basic Section 42020:Veterinary medical science-related
• Research Institution: Obihiro University of Agriculture and Veterinary Medicine
• Principal Investigator: 横山 直明 帯広畜産大学, 原虫病研究センター, 教授 (80301802)
• Co-Investigator(Kenkyū-buntansha): TUVSHINTULGA BUMDUUREN 帯広畜産大学, 原虫病研究センター, 外国人特別研究員
• Project Period (FY): 2018-10-12 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 2020: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2019: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2018: ¥600,000 (Direct Cost: ¥600,000)
• Keywords: ヒトバベシア病 / Babesia microti / Clofazimine / Tafenoquine / Artesunate / Atovaquone / 併用治療法 / ジミナゼンアセテート / MMV021057 / MMV675968 / 多剤併用治療法 / 耐性 / バベシア / 耐性原虫

Outline of Annual Research Achievements

バベシア原虫（Babesia microti）の感染に起因するヒトバベシア病は、アメリカ、ヨーロッパ、アジアの国々で報告が広がっており、新たな新興感染症として注目されている。しかしながら、本原虫病に対する効果的で、低コストで、低毒性の治療薬が未だ確立されていない。そこで、マウス感染モデル評価系を用いて、既存薬剤（Atovaquone：アトバコン）が効かないヒトバベシア病にも対峙できる併用治療法を開発する。具体的には、１）感染原虫を迅速に排除でき、２）安全に長期間の薬剤効果を持続でき、３）アドバコン治療から出現する耐性原虫に対しても効果を示し、かつ４）容易に耐性原虫の出現を許さない多剤併用治療法の確立を目指す。

最終年度では、１）Clofazimine（クロファジミン）は、免疫不全状態の宿主においてもB. microti感染に対して効果的であること、２）Tafenoquine（タフェノキン）とArtesunate（アルテスネイト）との併用療法がB. microtiに対して効果的な治療効果を誘導すること、及び３）Phyllanthus emblicaの果実には抗バベシア活性を示す因子が含まれることを明らかにした。これらの成果より、既存薬剤（アトバコン）が効かないヒトバベシア病にも対峙できる併用治療法を開発する上で有益な知見を得ることができた。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Oswaldo Cruz Institute(ブラジル)
• [Int'l Joint Research] Institute of Veterinary Medicine(モンゴル)
• [Int'l Joint Research] Tufts Medical Center/Yale School(米国)
• [Int'l Joint Research] Veterinary Research Institute(スリランカ)
• [Int'l Joint Research] モンゴル生命科学大学・獣医学研究所(モンゴル)
• [Int'l Joint Research] 国立獣医学研究所(スリランカ)
• [Int'l Joint Research] IPB大学・獣医学部/Balai Veteriner Subang(インドネシア)
• [Int'l Joint Research] Mansoura大学/Damanhour大学(エジプト)
• [Int'l Joint Research] Makerere大学(ウガンダ)
• [Int'l Joint Research] モンゴル生命科学大学・獣医学研究所(モンゴル)
• [Int'l Joint Research] Bogor農業大学(インドネシア)
• [Int'l Joint Research] Mansoura大学/Damanhour大学(エジプト)
• [Int'l Joint Research] Makerere大学(ウガンダ)
• [Journal Article] Activities of artesunate-based combinations and tafenoquine against Babesia bovis in vitro and Babesia microti in vivo (2020)
  • Author(s): Carvalho Leonardo J. M.、Tuvshintulga Bunduurem、Nugraha Arifin B.、Sivakumar Thillaiampalam、Yokoyama Naoaki
  • Journal Title: Parasites & Vectors Volume: 13 Issue: 1
  • DOI: 10.1186/s13071-020-04235-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clofazimine, a promising drug for the treatment of Babesia microti infection in severely immunocompromised hosts (2020)
  • Author(s): Tuvshintulga Bumduuren、Vannier Edouard、Tayebwa Dickson S、Gantuya Sambuu、Sivakumar Thillaiampalam、Guswanto Azirwan、Krause Peter J、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: The Journal of Infectious Diseases Volume: - Issue: 6 Pages: 1027-1036
  • DOI: 10.1093/infdis/jiaa195
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of ethanol and water extracts from Phyllanthus emblica fruits on the growth of bovine Babesia and equine piroplasma parasites in vitro and Babesia microti in mice. (2020)
  • Author(s): Tuvshintulga, B., Kawaguchi, R., Batmagnai, E., Kothalawala, H., Guanasekara, E., Banzragchgarav, O., Nugraha, A.B., Otgonsuren, D., Silva, S.S.P., Sivakumar, T., and Yokoyama, N.
  • Journal Title: Jpn. J. Vet. Parasitol. Volume: 19 Pages: 21-29
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular epidemiological survey of Babesia bovis, Babesia bigemina, and Babesia sp. Mymensingh infections in Mongolian cattle (2020)
  • Author(s): Otgonsuren Davaajav、Sivakumar Thillaiampalam、Tuvshintulga Bumduuren、Yokoyama Naoaki et al.
  • Journal Title: Parasitology International Volume: 77 Pages: 102107-102107
  • DOI: 10.1016/j.parint.2020.102107
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Host range and geographical distribution of Babesia sp. Mymensingh (2020)
  • Author(s): Sivakumar Thillaiampalam、Tuvshintulga Bumduuren、Kothalawala Hemal、Silva Seekkuge Susil Priyantha、Lan Dinh Thi Bich、Long Phung Thang、Yba?ez Adrian Patalinghug、Yba?ez Rochelle Haidee Daclan、Francisco Benitez Daniel、Tayebwa Dickson Stuart、DE Macedo Alan Caine Costa、Schnittger Leonhard、Yokoyama Naoaki
  • Journal Title: Transboundary and Emerging Diseases Volume: - Pages: 2233-2239
  • DOI: 10.1111/tbed.13546
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discovery of a new Theileria sp. closely related to Theileria annulata in cattle from Sri Lanka (2019)
  • Author(s): Sivakumar Thillaiampalam、Fujita Shiori、Tuvshintulga Bumduuren、Kothalawala Hemal、Silva Seekkuge Susil Priyantha、Yokoyama Naoaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1
  • DOI: 10.1038/s41598-019-52512-y
  • NAID: 120006769784
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Screening the Medicines for Malaria Venture Pathogen Box against piroplasm parasites (2019)
  • Author(s): Nugraha Arifin Budiman、Tuvshintulga Bumduuren、Guswanto Azirwan、Tayebwa Dickson Stuart、Rizk Mohamed Abdo、Gantuya Sambuu、El-Saber Batiha Gaber、Beshbishy Amany Magdy、Sivakumar Thillaiampalam、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: International Journal for Parasitology: Drugs and Drug Resistance Volume: 10 Pages: 84-90
  • DOI: 10.1016/j.ijpddr.2019.06.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of unstable resistance to diminazene aceturate in Babesia bovis (2019)
  • Author(s): Tuvshintulga Bumduuren、Sivakumar Thillaiampalam、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: International Journal for Parasitology: Drugs and Drug Resistance Volume: 9 Pages: 87-92
  • DOI: 10.1016/j.ijpddr.2019.02.001
  • NAID: 120006603076
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice (2018)
  • Author(s): Guswanto Azirwan、Nugraha Arifin Budiman、Tuvshintulga Bumduuren、Tayebwa Dickson Stuart、Rizk Mohamed Abdo、Batiha Gaber El-Saber、Gantuya Sambuu、Sivakumar Thillaiampalam、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: International Journal for Parasitology: Drugs and Drug Resistance Volume: 8 Issue: 1 Pages: 104-111
  • DOI: 10.1016/j.ijpddr.2018.02.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The effects of nitidine chloride and camptothecin on the growth of Babesia and Theileria parasites (2018)
  • Author(s): Tayebwa Dickson Stuart、Tuvshintulga Bumduuren、Guswanto Azirwan、Nugraha Arifin Budiman、Batiha Gaber El-Saber、Gantuya Sambuu、Rizk Mohamed Abdo、Vudriko Patrick、Sivakumar Thillaiampalam、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: Ticks and Tick-borne Diseases Volume: 9 Issue: 5 Pages: 1192-1201
  • DOI: 10.1016/j.ttbdis.2018.04.019
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Expressing of Green Fluorescent Protein in intraerythrocytic stage of Theileria equi (2019)
  • Author(s): Arifin Nugraha，Bumduuren Tuvshintulga，Ming Ming Liu，Xuenan Xuan，Naoaki Yokoyama，Ikuo Igarashi
  • Organizer: 第60回熱帯医学会大会
• [Presentation] Development of unstable resistance to diminazene aceturate in Babesia bovis (2019)
  • Author(s): Bumduuren Tuvshintulga，Thillaiampalam Sivakumar，Naoaki Yokoyama，Ikuo Igarashi
  • Organizer: 第60回熱帯医学会大会
• [Remarks] 帯広畜産大学・原虫用研究センター
  • URL: https://www.obihiro.ac.jp/facility/protozoa/
• [Remarks] OIE Reference Centres
  • URL: https://www.obihiro.ac.jp/facility/protozoa/en/oie-reference-centres
• [Remarks] 帯広畜産大学・原虫病研究センター
  • URL: https://www.obihiro.ac.jp/facility/protozoa/