Functional analysis of PfEMP domains with the endothelial cell surface protein array

• Project/Area Number: 18H02651
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49040:Parasitology-related
• Research Institution: Ehime University
• Principal Investigator: Takashima Eizo 愛媛大学, プロテオサイエンスセンター, 准教授 (50366762)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 重症マラリア / PfEMP1 / タンパク質相互作用 / マラリア / 重症化機構 / コムギ無細胞系 / タンパク質-タンパク質相互作用 / 血管内皮細胞

Outline of Final Research Achievements

Plasmodium falciparum parasites possess 62 var genes that encode about 271 PfEMP1 domains. The binding of these domains to endothelial cell surface proteins causes erythrocytes sequestration, which leads to complicated malaria. We recently expressed all of the domains with a wheat germ cell-free system and identified 17 domains whose antibodies levels negatively correlate with reduced risk to symptomatic disease in a malaria exposed population. Therefore, understanding the role of these 17 domains in host-parasite interactions is of great interest in elucidating the factors underlying complicated malaria. To this end, this study used 17 PfEMP1 domains to comprehensively screen a library of endothelial cell surface proteins for potential interacting partners. Top hits were evaluated for interaction using SPR and pull-down assays. As an outcome, we successfully identified and confirmed that a novel human protein interacts with one of the potentially sero-protective PfEMP1 domain.

Academic Significance and Societal Importance of the Research Achievements

熱帯熱マラリアは毎年40万人以上が死亡する重篤な感染症である。重症マラリアは昏睡・重症貧血等を合併した熱帯熱マラリアであり、高い致死率が問題となっている。成熟した原虫の寄生する赤血球が末梢血管壁に接着するシークエストレーションは、重症マラリアの発症に直接関与していると考えられている。そのためこの分子メカニズムを明らかにすることが重要である。本研究では感染赤血球表面の原虫タンパク質が認識する、新たなヒトタンパク質の探索に成功した。これは重症マラリア治療法の開発や、新規マラリアワクチンの開発などに発展できる成果である。

Research Products

• [Journal Article] Identification of a Novel RAMA/RON3 Rhoptry Protein Complex in Plasmodium falciparum Merozoites (2021)
  • Author(s): Ito Daisuke、Chen Jun-Hu、Takashima Eizo、Hasegawa Tomoyuki、Otsuki Hitoshi、Takeo Satoru、Thongkukiatkul Amporn、Han Eun-Taek、Tsuboi Takafumi
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 10 Pages: 296-296
  • DOI: 10.3389/fcimb.2020.605367
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of a Plasmodium falciparum PHISTc protein, PF3D7_0801000, in blood- stage malaria parasites (2021)
  • Author(s): Nagaoka Hikaru、Kanoi Bernard N.、Morita Masayuki、Nakata Takahiro、Palacpac Nirianne M.Q.、Egwang Thomas G.、Horii Toshihiro、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Parasitology International Volume: 80 Pages: 102240-102240
  • DOI: 10.1016/j.parint.2020.102240
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Leveraging the wheat germ cell-free protein synthesis system to accelerate malaria vaccine development (2021)
  • Author(s): Kanoi Bernard N.、Nagaoka Hikaru、Morita Masayuki、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Parasitology International Volume: 80 Pages: 102224-102224
  • DOI: 10.1016/j.parint.2020.102224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PV1 Protein from Plasmodium falciparum Exhibits Chaperone-Like Functions and Cooperates with Hsp100s (2020)
  • Author(s): Hakamada Kazuaki、Nakamura Manami、Midorikawa Rio、Shinohara Kyosuke、Noguchi Keiichi、Nagaoka Hikaru、Takashima Eizo、Morishima Ken、Inoue Rintaro、Sugiyama Masaaki、Kawamoto Akihiro、Yohda Masafumi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 22 Pages: 8616-8616
  • DOI: 10.3390/ijms21228616
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamin 1 is important for microtubule organisation and stabilisation in glomerular podocytes (2020)
  • Author(s): The Mon La , Tachibana, H., Li, S.A., Abe, T., Seiriki, S., Nagaoka, H., Takashima, E., Takeda, T., Ogawa, D., Makino, S., Asanuma, K., Watanabe, M., Tian, X., Ishibe, S., Sakane, A., Sasaki, T., Wada, J., Takei, K., Yamada, H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 12 Pages: 16449-16463
  • DOI: 10.1096/fj.202001240rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development and validation of serological markers for detecting recent Plasmodium vivax infection (2020)
  • Author(s): Longley Rhea J.、White Michael T.、Takashima Eizo et al
  • Journal Title: Nature Medicine Volume: 26 Issue: 5 Pages: 741-749
  • DOI: 10.1038/s41591-020-0841-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antibodies against a short region of PfRipr inhibit Plasmodium falciparum merozoite invasion and PfRipr interaction with Rh5 and SEMA7A (2020)
  • Author(s): Nagaoka Hikaru、Kanoi Bernard N.、Ntege Edward H.、Aoki Masamitsu、Fukushima Akihisa、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-020-63611-6
  • Peer Reviewed / Open Access
• [Journal Article] The malaria parasite Plasmodium falciparum in red blood cells selectively takes up serum proteins that affect host pathogenicity (2020)
  • Author(s): Tougan Takahiro、Edula Jyotheeswara R.、Morita Masayuki、Takashima Eizo、Honma Hajime、Tsuboi Takafumi、Horii Toshihiro
  • Journal Title: Malaria Journal Volume: 19 Issue: 1 Pages: 155-155
  • DOI: 10.1186/s12936-020-03229-1
  • Peer Reviewed / Open Access
• [Journal Article] Global repertoire of human antibodies against Plasmodium falciparum RIFINs, SURFINs, and STEVORs in a malaria exposed population (2020)
  • Author(s): Kanoi Bernard N.、Nagaoka Hikaru、Morita Masayuki、White Michael T.、Palacpac Nirianne M.Q.、Ntege Edward H.、Balikagala Betty、Yeka Adoke、Egwang Thomas G.、Horii Toshihiro、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Frontiers in Immunology Volume: "" Pages: 1-12
  • DOI: 10.3389/fimmu.2020.00893
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PfMSA180 is a novel Plasmodium falciparum vaccine antigen that interacts with human erythrocyte integrin associated protein (CD47) (2019)
  • Author(s): Nagaoka Hikaru、Sasaoka Chisa、Yuguchi Takaaki、Kanoi Bernard N.、Ito Daisuke、Morita Masayuki、Udomsangpetch Rachanee、Sattabongkot Jetsumon、Ishino Tomoko、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5923-5923
  • DOI: 10.1038/s41598-019-42366-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The N-Terminal Region of Plasmodium falciparum MSP10 Is a Target of Protective Antibodies in Malaria and Is Important for PfGAMA/PfMSP10 Interaction (2019)
  • Author(s): Nagaoka Hikaru、Kanoi Bernard N.、Jinoka Kana、Morita Masayuki、Arumugam Thangavelu U.、Palacpac Nirianne M. Q.、Egwang Thomas G.、Horii Toshihiro、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2669-2669
  • DOI: 10.3389/fimmu.2019.02669
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-MSP11 IgG inhibits Plasmodium falciparum merozoite invasion into erythrocytes in vitro (2019)
  • Author(s): Tohmoto Tatsuhiro、Takashima Eizo、Takeo Satoru、Morita Masayuki、Nagaoka Hikaru、Udomsangpetch Rachanee、Sattabongkot Jetsumon、Ishino Tomoko、Torii Motomi、Tsuboi Takafumi
  • Journal Title: Parasitology International Volume: 69 Pages: 25-29
  • DOI: 10.1016/j.parint.2018.10.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comprehensive analysis of antibody responses to Plasmodium falciparum erythrocyte membrane protein 1 domains (2018)
  • Author(s): Kanoi Bernard N.、Nagaoka Hikaru、Morita Masayuki、White Michael T.、Palacpac Nirianne M.Q.、Ntege Edward H.、Balikagala Betty、Yeka Adoke、Egwang Thomas G.、Horii Toshihiro、Tsuboi Takafumi、Takashima Eizo
  • Journal Title: Vaccine Volume: 36 Issue: 45 Pages: 6826-6833
  • DOI: 10.1016/j.vaccine.2018.08.058
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 熱帯熱マラリア原虫 MSP10の赤血球侵入におけるメカニズムの解明 (2020)
  • Author(s): 長岡ひかる、カノイ バーナード、神岡花奈、森田将之、ニリアン パラクパック、堀井俊宏、坪井敬文、高島英造
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] 熱帯熱マラリア原虫メロゾイトのデンスグラニュール分子LSA3の性状解析 (2020)
  • Author(s): 森田将之、 Jennison Charlie、石野智子、 O'Neill Matthew、Boddey Justin A.、高島英造、坪井敬文
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] マンソン裂頭条虫由来plerocercoid immunosuppressive factorの分子クローニングとキャラクタリゼーション (2020)
  • Author(s): 近藤陽子、伊藤大輔、蓼本早百合、伊丹菜菜瀬、西方修馬、高島英造、坪井敬文、福本宗嗣、大槻 均
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] Identification of functional domains in Pfs230 based transmission blocking vaccines (2020)
  • Author(s): 三浦憲豊、橘 真由美、高島英造、森田将之、長岡ひかる、Pham Thao、 Long Carole、 King Richter、鳥居本美、石野智子、坪井敬文
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] 熱帯熱マラリア発症阻止に関連する感染赤血球表面抗原のゲノム網羅的免疫スクリーニング (2020)
  • Author(s): 高島英造、カノイ バーナード、長岡ひかる、パラックパック ニリアン、堀井俊宏、坪井敬文
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] 三日熱マラリアヒプノゾイト保有者の血清診断マーカーの開発と検証 (2020)
  • Author(s): 坪井敬文、高島英造、森田将之、 Longley Rhea、 White Michael、Harbes Matthias、 Ding Xavier、 Mueller Ivo
  • Organizer: 第89回日本寄生虫学会大会、帯広市、誌上開催、5/30-31、2020
• [Presentation] 新規マラリアワクチン候補GAMAに対する侵入阻害抗体の作製 (2020)
  • Author(s): 開曾我郁弥、徳永聡、小澤龍彦、長岡ひかる、高島英造、岸裕幸、村口篤、坪井敬文、 澤崎達也
  • Organizer: 第61回 日本生化学会中国・四国支部例会 7/13-20、2020
• [Presentation] Genome-scale analysis of naturally acquired antibody responses to PfEMP1 domains (2020)
  • Author(s): Kanoi BN, Nagaoka H, Morita M, White MT, Palacpac NMQ, Ntege EH, Balikagala B
  • Organizer: U.S.-Japan Cooperative Medical Sciences Program (USJCMSP), The 50th Joint Conference on Parasitic Diseases, Matsuyama, Japan
  • Int'l Joint Research
• [Presentation] Screening for background immunity to P. vivax malaria in volunteers (2019)
  • Author(s): Takashima E, Tsuboi T
  • Organizer: MIST (Malaria Infection Study in Thailand) Kick-off Meeting, Bangkok, Thailand,
  • Int'l Joint Research / Invited
• [Presentation] Defining naturally acquired antibody kinetics against Plasmodium vivax antigens in a region of low malaria transmission in western Thailand. (2019)
  • Author(s): Liu Z, Takashima E, Harbers M, Tsuboi T, White M, Sattabongkot J, Longley R, Mueller I
  • Organizer: 7th International Conference on Plasmodium vivax Research, Paris, France,
  • Int'l Joint Research
• [Presentation] Association between antibody responses to Plasmodium vivax and protection against clinical malaria in a longitudinal cohort of Papua New Guinean children. (2019)
  • Author(s): Mazhari R, Kanoi BN, White M, Takashima E, Nagaoka H, Longley R, Tsuboi T, Mueller I
  • Organizer: 7th International Conference on Plasmodium vivax Research, Paris, France,
  • Int'l Joint Research
• [Presentation] Comprehensive serological profiles of P. falciparum VSA and risk of febrile malaria in Uganda. (2019)
  • Author(s): Kanoi BN, Nagaoka H, Palacpac NMQ, White MT, Morita M, Ntege EH, Balikagala B, Yeka A, Egwang TG, Horii T, Tsuboi T, Takashima E.
  • Organizer: The 17th Protein Island Matsuyama (PIM) International Symposium, Matsuyama, Japan
  • Int'l Joint Research
• [Presentation] The N-terminal region of Plasmodium falciparum MSP10 is important for PfGAMA/MSP10 interaction and is a target of protective antibodies. (2019)
  • Author(s): Nagaoka H, Kanoi BN, Jinoka K, Morita M, Arumugam TU, Palacpac NMQ, Egwang TG, Horii T, Tsuboi T, Takashima E
  • Organizer: ASTMH 68th annual meeting, Washington DC, USA
  • Int'l Joint Research
• [Presentation] Human antibody repertoires to RIFINs and STEVORs associate with reduced risk to febrile malaria. (2019)
  • Author(s): Kanoi BN, Nagaoka H, Palacpac NMQ, White MT, Morita M, Ntege EH, Balikagala B, Yeka A, Egwang TG, Horii T, Tsuboi T, Takashima E
  • Organizer: ASTMH 68th annual meeting, Washington DC, USA
  • Int'l Joint Research
• [Presentation] Naturally acquired antibody responses to PfEMP1 domains reveal potential protective targets of immunity in malaria (2018)
  • Author(s): Kanoi BN, Nagaoka H, Morita M, White MT, Palacpac NMQ, Ntege EH, Balikagala B, Yeka A, Egwang TG, Horii T, Tsuboi T, Takashima E
  • Organizer: 14th International Congress of Parasitology, Daegu City, Korea, August 19-24, 2018
  • Int'l Joint Research
• [Presentation] Post-genomic strategies for the identification of novel blood-stage vaccine candidates with wheat germ cell-free system. (2018)
  • Author(s): Takashima E
  • Organizer: 14th International Congress of Parasitology, Daegu City, Korea, August 19-24, 2018
  • Int'l Joint Research / Invited
• [Presentation] Comprehensive analysis of antibody responses to full-length PfEMP1 domains (2018)
  • Author(s): Takashima E, Kanoi BN, Nagaoka H, Morita M, White MT, Palacpac NMQ, Ntege EH, Balikagala B, Yeka A, Egwang TG, Horii T, Tsuboi T.
  • Organizer: ASTMH 67th annual meeting, New Orleans, USA, October 28-November 1, 2018.
  • Int'l Joint Research
• [Presentation] 無細胞タンパク質ライブラリーによる次世代マラリア研究 (2018)
  • Author(s): 高島英造
  • Organizer: シンポジウム：寄生の生化学、第91回日本生化学会大会、京都市、9/24-26、2018。
  • Int'l Joint Research / Invited
• [Remarks] マラリア研究部門HP
  • URL: http://www.pros.ehime-u.ac.jp/malaria/
• [Remarks] 愛媛大学 プロテオサイエンスセンター マラリア研究部門
  • URL: http://www.pros.ehime-u.ac.jp/malaria/
• [Remarks] 愛媛大学プロテオサイエンスセンター マラリア研究部門
  • URL: http://www.pros.ehime-u.ac.jp/malaria/