Molecular pathological analysis of infectious disease development using gain-of-function STAT1 knock-in mice.

• Project/Area Number: 17K10112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Tsumura Miyuki 広島大学, 医系科学研究科(医), 研究員 (80646274)
• Co-Investigator(Kenkyū-buntansha): 岡田 賢 広島大学, 医系科学研究科(医), 教授 (80457241)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Stat1ノックインマウス / 慢性皮膚粘膜カンジダ症 / STAT1機能獲得型変異 / 疾患モデルマウス / Stat1 / 機能獲得型変異

Outline of Final Research Achievements

Patients with gain-of-function (GOF)-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to chronic mucocutaneous candidiasis (CMC), and those with severe infections and/or autoimmunity have a poor prognosis. In this study, we generated GOF-Stat1R274Q mice to better understand the disease pathogenesis caused by GOF-STAT1 mutations in humans. The mice replicated the human molecular and cellular phenotypes by presenting with hyperphosphorylation of STAT1 upon cytokine stimulation and impairment of Th17 cells in the small intestine. Moreover, GOF-Stat1R274Q mice might show slightly increased susceptibility to C. albicans infection, probably because of impaired IL-17-based immunity. The GOF-Stat1R274Q mice established here should be a useful model to understand the human primary immunodeficiency disease caused by GOF-STAT1 mutations.

Academic Significance and Societal Importance of the Research Achievements

本研究ではGOF-Stat1R274QマウスでのC. albicans排除障害にTh17分化障害が重要な役割を果たすとともに、今回樹立したGOF-Stat1R274QマウスはTh17免疫応答を中心とした、CMCDの病態解明に有用であることを示した。今後は本症で多彩な感染症を発症する病態を更に解明するために、GOF-Stat1R274Qマウスを用いて、C. albicans以外の病原体としてマイコバクテリアやヘルペスなどの感染実験を行うことが必要であると考えられる。それによって、本症患者のさらなる病態解明が進むとともに、新規の治療法の開発につながることが期待される。

Research Products

• [Journal Article] Downregulation of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in a co-culture system with human stimulated X-linked CGD neutrophils (2020)
  • Author(s): Nakamura-Utsunomiya Akari、Tsumura Miyuki、Okada Satoshi、Kawaguchi Hiroshi、Kobayashi Masao
  • Journal Title: PLOS ONE Volume: 15 Issue: 4 Pages: e0230665-e0230665
  • DOI: 10.1371/journal.pone.0230665
  • Peer Reviewed / Open Access
• [Journal Article] Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice (2019)
  • Author(s): Tamaura Moe、Satoh-Takayama Naoko、Tsumura Miyuki、Sasaki Takaharu、Goda Satoshi、Kageyama Tomoko、Hayakawa Seiichi、Kimura Shunsuke、Asano Takaki、Nakayama Manabu、Koseki Haruhiko、Ohara Osamu、Okada Satoshi、Ohno Hiroshi、Kobayashi Masao
  • Journal Title: International Immunology Volume: － Issue: 4 Pages: 259-272
  • DOI: 10.1093/intimm/dxz079
  • Peer Reviewed / Open Access
• [Journal Article] Gain-of-function IKBKB mutation causes human combined immune deficiency (2018)
  • Author(s): Cardinez C, Miraghazadeh B, Tanita K, da Silva E, Hoshino A, Okada S, Chand R, Asano T, Tsumura M, Yoshida K, Ohnishi H, Kato Z, Yamazaki M, Okuno Y, Miyano S, Kojima S, Ogawa S, Andrews TD, Field MA, Burgio G,et al.
  • Journal Title: J Exp Med Volume: 215 Issue: 11 Pages: 2715-2724
  • DOI: 10.1084/jem.20180639
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome (2018)
  • Author(s): Asano Takaki、Okada Satoshi、Tsumura Miyuki、Yeh Tzu-Wen、Mitsui-Sekinaka Kanako、Tsujita Yuki、Ichinose Youjiro、Shimada Akira、Hashimoto Kunio、Wada Taizo、Imai Kohsuke、Ohara Osamu、Morio Tomohiro、Nonoyama Shigeaki、Kobayashi Masao
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 568-568
  • DOI: 10.3389/fimmu.2018.00568
  • NAID: 120006473827
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection (2018)
  • Author(s): Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S, Mandel H, Garcia P, Ciancanelli MJ, Biran A, Lafaille FG, Tsumura M, et al.
  • Journal Title: Cell Volume: 172 Issue: 5 Pages: 952-965.e18
  • DOI: 10.1016/j.cell.2018.02.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Newborn screening for carnitine palmitoyltransferase II deficiency using (C16 + C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity (2017)
  • Author(s): Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Maruyama S, Noguchi A, Awaya T, Ishige N, Musha I, Ajihara S, Ohtake A, Naito E, Hamada Y, Kono T, Asada T, Sasaio H, Fukaoo T, Fujikip R, Ohara O, Bo R, Yamada K, Kobayashi H, Hasegawa Y, Yamaguchi S, Takayanagis M, Hata I, Shigematsu Y, Kobayashi M
  • Journal Title: Molecular Genetics and Metabolism Volume: 122 Issue: 3 Pages: 67-75
  • DOI: 10.1016/j.ymgme.2017.07.011
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. (2017)
  • Author(s): Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H, Yamashita M, Okano T, Tsumura M, Nishimura S, Sakata S, Kobayashi M, Nakamura H, Kamizono J, Mitsui-Sekinaka K, Ichimura T, Ohga S, Nakazawa Y, Takagi M, Imai K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Kojima S, Nonoyama S, Morio T, Kanegane H.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 1 Pages: 390-400
  • DOI: 10.1016/j.jaci.2016.09.029
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants (2016)
  • Author(s): Kagawa R, Fujiki R, Tsumura M, Sakata S, Nishimura S,Itan Y, Kong XF, Kato Z, Ohnishi H, Hirata O, Saito S, Ikeda M,Baghdadi JE, Bousfiha A, Fujiwara K, Oleastro M, Yancoski J,Perez L, Danielian S, Ailal F, Takada H, Hara T, Anne Puel A, Boisson-Dupuis S, Bustamante J, Casanova JL, Ohara O, Okada S, Masao Kobayashi M.
  • Journal Title: J Allergy Clin Immunol. Volume: － Issue: 1 Pages: 232-241
  • DOI: 10.1016/j.jaci.2016.09.035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 本邦初の常染色体劣性遺伝STAT1完全欠損症 (2020)
  • Author(s): 坂田園子、岡田賢、松林正、玉浦萌、津村弥来、唐川修平、岡野翼、今井耕輔、森尾友宏、Jean-Laurent Casanova、小林正夫
  • Organizer: 第3回日本免疫不全・自己炎症学会総会・学術集会
• [Presentation] Exophiala dermatitidisによる全身性黒色真菌感染症を発症したCARD9欠損症の一例 (2019)
  • Author(s): 今中雄介、岡田賢、長岡里枝、谷口真紀、下村麻衣子、津村弥来、唐川修平、土居岳彦、小林正夫
  • Organizer: 第47回日本臨床免疫学会総会
• [Presentation] A mouse model of human disease caused by gain-of-function STAT1 mutation (2019)
  • Author(s): Moe Tamaura，Naoko Satoh，Miyuki Tsumura，Takaharu Sasaki， Shunsuke Kimura，Tomoko Kageyama，Seiichi Hayakawa， Takaki Asano，Satoshi Goda，Manabu Nakayama，Haruhiko Koseki， Osamu Ohara，Satoshi Okada，Hiroshi Ohno，Masao Kobayashi
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] The first intronic mutations which caused autosomal recessive complete STAT1 deficiency (2019)
  • Author(s): Sonoko Sakata,Satoshi Okada,Tadashi Matsubayashi,Moe Tamaura,Miyuki Tsumura,Tsubasa Okano,Kosuke Imai, Jacinta Bustamante,Tomohiro Morio,Jean-Laurent Casanova, Masao Kobayashi
  • Organizer: The 2019 Focused Meeting og the European Society for Immunodeficiencies
  • Int'l Joint Research
• [Presentation] A mouse model of human disease caused by gain-of-function STAT1 mutation (2019)
  • Author(s): Moe Tamaura, Naoko Satoh-Takayama, Miyuki Tsumura, Takaharu Sasaki, Satoshi Goda, Tomoko Kageyama, Seiichi Hayakawa, Shunsuke Kimura, Takaki Asano, Manabu Nakayama, Haruhiko Koseki, Osamu Ohara, Satoshi Okada, Hiroshi Ohno , Masao Kobayashi
  • Organizer: The 2019 Focused Meeting og the European Society for Immunodeficiencies
  • Int'l Joint Research
• [Presentation] ELANE変異アレル破壊による遺伝子治療の検討 (2019)
  • Author(s): 岡田賢、今中雄介、津村弥来、落合博、中田慎一郎、小原收、山本卓、小林正夫
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] アンチセンス核酸によるG6PC高頻度スプライシング変異の発現修復 (2019)
  • Author(s): 但馬 剛、津村 弥来、岡田 賢、小比賀 聡
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] 全国施行が実現したCPT2欠損症マススクリーニングの現状報告 (2019)
  • Author(s): 但馬 剛、原 圭一、香川 礼子、宇都宮 朱里、津村 弥来、岡田 賢、湯浅 光織、畑 郁江、重松 陽介、山口 清次
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] 標識脂肪酸負荷末梢血単核球中のアシルカルニチン比による脂肪酸代謝異常症の診断 (2019)
  • Author(s): 湯浅 光織、畑 郁江、杉原 啓一、磯崎 由宇子、重松 陽介、大嶋 勇成、津村 弥来、香川 礼子、岡田 賢、原 圭一、但馬 剛
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] ELANE変異アレル破壊による遺伝子治療の検討 (2019)
  • Author(s): 岡田 賢、今中 雄介、津村 弥来、落合 博、中田 慎一郎、小原 收、山本 卓、小林 正夫
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] Gain-of-function IKBKB mutation causes human combined immune deficiency (2019)
  • Author(s): K. Tanita, C Cardinez, B. Miraghanzadeh, A. Hoshino, S. Okada, T. Asano, M. Tsumura, H. Ohnishi, Z. Kato, T. Morio, C.G. Vinuesa, H. Kanegane, M.C. Cook
  • Organizer: 第2回日本免疫不全・自己炎症学会
• [Presentation] IKBKB機能獲得変異による新奇遅発発症複合免疫不全症 (2018)
  • Author(s): 谷田 けい、星野 顕宏、岡田 賢、浅野 孝基、津村 弥来、大西 秀典、加藤 善一郎、山崎 雅英、森尾 友宏、金兼 弘和
  • Organizer: 第46回日本臨床免疫学会
• [Presentation] 抗N-methyl-D-aspartate(NMDA)受容体脳炎を契機に診断に至ったIRAK4欠損症 (2018)
  • Author(s): 浅野 孝基、西村 志帆、小林 良行、津村 弥来、石川 暢恒、大西 秀典、高田 英俊、Sancho-Shimizu Vanessa、森谷 邦彦、Puel Anne、Picard Capucine、Irani Sarosh R.、Casanova Jean-Laurent、岡田 賢、小林 正夫
  • Organizer: 第46回日本臨床免疫学会
• [Presentation] 新指標(C16+C18:1)/C2 & C14/C3によるCPT2欠損症の新生児マススクリーニング (2018)
  • Author(s): 但馬 剛、原 圭一、津村 弥来、香川 礼子、岡田 賢、湯浅 光織、畑 郁江、重松 陽介、山口 清次
  • Organizer: 第60回日本先天代謝異常学会
• [Presentation] アンチセンス核酸によるG6PCスプライシング変異c.648G>Tの発現修復 (2018)
  • Author(s): 但馬 剛、岡田 賢、津村 弥来
  • Organizer: 第60回日本先天代謝異常学会
• [Presentation] Anti-Methyl-D-Aspartate Receptor Encephalitis Associated with IRAK4 Deficiency (2018)
  • Author(s): T. Asano, S. Nishimura, Y. Kobayashi, M. Tsumura, N. Ishikawa, H. Ohnishi, H. Takada, V. Sancho-Shimizu, K. Moriya, A. Puel, C. Picard, S.R. Irani, J.L. Casanova, S. Okada, M. Kobayashi
  • Organizer: 18th European Society for Immunodeficiencies
  • Int'l Joint Research
• [Presentation] CPT2欠損症スクリーニング新指標の有用性 最近の診断例を加えた検討 (2018)
  • Author(s): 但馬 剛、原 圭一、香川 礼子、津村 弥来、岡田 賢、湯浅 光織、畑 郁江、重松 陽介、山口 清次
  • Organizer: 第45回日本マス・スクリーニング学会学術集会