Comprehensive elucidation of fitness cost in drug-resistant malaria parasites through while life cycle

• Project/Area Number: 16K08765
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Parasitology (including sanitary zoology)
• Research Institution: Juntendo University
• Principal Investigator: Tachibana Shin-Ichiro 順天堂大学, 医学部, 助教 (90414630)
• Co-Investigator(Kenkyū-buntansha): 平井 誠 順天堂大学, 医学部, 准教授 (50326849)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: マラリア原虫 / 薬剤耐性 / 適応度 / 種内競争 / アルテミシニン

Outline of Final Research Achievements

Acquisition of drug resistance with gene mutations generally raises decrease of fitness in organisms, and therefore, the drug resistance may be disadvantageous under conditions without the drug. To assess fitness costs imposed by resistant to sulfadoxine (SX) alone, we comprehensively evaluated parasite fitness within-hosts and within-vectors using a transgenic rodent malaria parasite Plasmodium berghei. Competitive experiments in which SX-resistant and wild-type parasites were co-infected into mice showed a similar growth rate. In contrast, growth rate was significantly greater in SX-resistant clones than that in wild-type clones within vectors. These observations suggest that acquisition of SX resistance did not alter the within-rodent fitness in the absence of the drug, whereas it unexpectedly provoked a fitness advantage within mosquitos.

Academic Significance and Societal Importance of the Research Achievements

一般的に、遺伝子変異によって薬剤耐性を獲得した病原体には、適応度の低下が見られる。しかしながら本研究によって、マラリア原虫では薬剤耐性の獲得が適応度の低下を引き起こさない事例があるという、これまでの常識を覆す知見が得られた。本研究成果は、今後も抗マラリア薬を持続的かつ効果的に利用するための方策を考える上で参照されるべきものであり、国際保健に貢献するものである。

Research Products

• [Journal Article] Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda (2020)
  • Author(s): Balikagala Betty、Sakurai-Yatsushiro Miki、Hirai Makoto et al
  • Journal Title: Malaria Journal Volume: 19 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12936-020-03157-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lack of significant recovery of chloroquine sensitivity in Plasmodium falciparum parasites following discontinuance of chloroquine use in Papua New Guinea (2018)
  • Author(s): Sekihara M, Tachibana S-I, Yamauchi M, Yatsushiro S, Tiwara S, Fukuda N, Ikeda M, Mori T, Hirai M, Hombhanje F, Mita T
  • Journal Title: Malaria Journal Volume: 17 Issue: 1 Pages: 434-434
  • DOI: 10.1186/s12936-018-2585-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Artemisinin-Resistant Plasmodium falciparum with High Survival Rates, Uganda, 2014-2016 (2018)
  • Author(s): Ikeda M, Kaneko M, Tachibana S-I, Balikagala B, Sakurai-Yatsushiro M, Yatsushiro S, Takahashi N, Yamauchi M, Sekihara M, Hashimoto M, Katuro OT, Olia A, Obwoya PS, Auma MA, Anywar DA, Odongo-Aginya EI, Okello-Onen J, Hirai M, Ohashi J, Palacpac NMQ, Kataoka M, Tsuboi T, Kimura E, Horii T, Mita T.
  • Journal Title: Emerging Infectious Diseases Volume: 24 Issue: 4 Pages: 718-726
  • DOI: 10.3201/eid2404.170141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Absence of in vivo selection for K13 mutations after artemether-lumefantrine treatment in Uganda. (2017)
  • Author(s): Balikagala B, Mita T, Ikeda M, Sakurai M, Yatsushiro S, Takahashi N, Tachibana SI, Auma M, Ntege EH, Ito D, Takashima E, Palacpac NM, Egwang TG, Onen JO, Kataoka M, Kimura E, Horii T, Tsuboi T.
  • Journal Title: Malar J. Volume: 16(1) Issue: 1 Pages: 1-23
  • DOI: 10.1186/s12936-016-1663-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations in Papua New Guinea (2019)
  • Author(s): Miotto O, Sekihara M, Tachibana S-I, Yamauchi M, Ikeda M, Mori T, Hirai M, Pearson R, Amato R, Goncalves S, Mueller I, Barry A, Noviyanti R, Ringwald P, Ohashi J, Hombhanje F, Kwiatkowski D, Mita T
  • Organizer: American Society of Tropical Medicine and Hygiene 68th Annual Meeting
  • Int'l Joint Research
• [Presentation] ウガンダ北部マラリア原虫集団におけるアルテミシニン耐性レベルの推移 (2019)
  • Author(s): 池田美恵, 金子恵, 橘真一郎, 山内祐人, Betty Balikagala, 江本桜子, 福田直到, 牧喜子, 森稔幸, 平井誠, 橋本宗明, Osbert T. Katuro, Mary Auma, Denis A. Anywar, Nirianne M. Q. Palacpac, 片岡正俊, Emmanuel I. Odongo-Aginya, 木村英作, 堀井俊宏, 美田敏宏
  • Organizer: 第88回日本寄生虫学会大会
• [Presentation] In-vivo artemisinin resistance may have emerged in Uganda (2019)
  • Author(s): Betty Balikagala, 池田美恵, 橘真一郎, 山内祐人, 福田直到, 関原誠, 江本桜子, Osbert T. Katuro, Opio Walter・Mary Auma, Denis A. Anywar, 森稔幸, 平井誠, 片岡正俊, Nirianne M. Q. Palacpac, Emmanuel I. Odongo-Aginya, 木村英作, 堀井俊宏, 美田敏宏
  • Organizer: 第88回日本寄生虫学会大会
• [Presentation] 蚊-マウスモデルにおけるサルファドキシン耐性マラリア原虫の適応度に関する研究 (2019)
  • Author(s): 山内祐人・平井誠・橘真一郎・森稔幸・美田敏宏
  • Organizer: 第88回日本寄生虫学会大会
• [Presentation] Prerequisite Emergence of Background Mutations for kelch13-related Artemisinin-Resistant Plasmodium falciparum isolates (2017)
  • Author(s): Tachibana S-I, Hirai M, Mori T, Mita T
  • Organizer: American Society of Tropical Medicine and Hygiene 66th Annual Meeting
  • Int'l Joint Research
• [Presentation] Isolation of piperaquine-resistant rodent malaria parasite from malaria mutator (2017)
  • Author(s): Hirai M, Ikeda M, Tachibana S-I, Mita T
  • Organizer: American Society of Tropical Medicine and Hygiene 66th Annual Meeting
  • Int'l Joint Research
• [Presentation] 高頻度突然変異マラリア原虫を用いた薬剤耐性機構解明への挑戦 (2016)
  • Author(s): 平井誠・池田美恵・橘真一郎・美田敏宏
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited