実験モデルを用いた肺非結核性抗酸菌症の疾患感受性遺伝子の機能解析

• Project/Area Number: 18J02173
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Respiratory organ internal medicine
• Research Institution: National Institute of Infectious Diseases
• Research Fellow: 朝倉 崇徳 国立感染症研究所, ハンセン病研究センター感染制御部, 特別研究員(PD)
• Project Period (FY): 2018-04-25 – 2021-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺非結核性抗酸菌症 / 気管支拡張症 / Mycobacterium avium / NTM / 肺MAC症

Outline of Annual Research Achievements

共同研究で実施している肺非結核性抗酸菌(NTM)症に関するゲノムワイド関連解析において候補SNPおよび疾患感受性遺伝子Xが同定された。肺NTM症の疾患感受性遺伝子Xが恒常的に検出されていることがデータベースで確認されている、ヒト上皮細胞株H292細胞株に対して、Mycobacterium avium subsp. Hominissuis (MAH)104株を感染させ、菌の細胞内への取り込みおよびその後の細胞内増殖の変化、疾患感受性遺伝子Xの変動を経時的に確認した。菌に関しては培養およびチールニールゼン染色で評価した。その後同様の実験をsiRNAによるknockdown(KD)、プラスミドによるoverexpression(OE)を試み施行した。それぞれの遺伝子のKDおよびOEは確認したものの、菌量および遺伝子発現の明確な差は検出できなかった。同様の実験をヒト気道上皮株であるBEAS2Bで施行したが、同様に明確な差が得られなかった。ヒト末梢血単核球細胞(PBMC)に対する経時的な感染実験においても候補遺伝子をいくつか検討したが、明確な上昇を得ることはできなかった。その後、Primary Human Bronchial Epithelial Cellsの培養系において遺伝子Xの発現を確認し、電気穿孔法を用いたCRISPR-Cas9およびgRNAの導入により遺伝子Xのノックアウト株の樹立に成功した。今後、気相液相界面培養(ALI)による分化後の変化を検討する予定である。また、同細胞の培養系において、レンチウイルスを用いた過剰発現の系も実施予定である。また、肺組織において同遺伝子の発現局在を確認した。今後は疾患肺との比較を行う予定である。

Research Progress Status

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Research Products

• [Int'l Joint Research] ノースカロライナ大学(米国)
• [Journal Article] ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice (2020)
  • Author(s): Suzuki Shoji、Ishii Makoto、Asakura Takanori、Namkoong Ho、Okamori Satoshi、Yagi Kazuma、Kamata Hirofumi、Kusumoto Tatsuya、Kagawa Shizuko、Hegab Ahmed E.、Yoda Masaki、Horiuchi Keisuke、Hasegawa Naoki、Betsuyaku Tomoko
  • Journal Title: American Journal of Physiology-Lung Cellular and Molecular Physiology Volume: -
  • DOI: 10.1152/ajplung.00214.2019
  • Peer Reviewed
• [Journal Article] Complete Genome Sequence of Mycobacterium xenopi JCM15661T, Obtained Using Nanopore and Illumina Sequencing Technologies. (2020)
  • Author(s): Yoshida M, Fukano H, Asakura T, Hisatsune J, Hoshino Y.
  • Journal Title: Microbiol Resour Announc Volume: 9 Pages: 0-0
  • DOI: 10.1128/mra.01583-19
  • Peer Reviewed / Open Access
• [Journal Article] Long-Lasting Response to Nivolumab for a Patient With Lynch Syndrome?Associated Lung Adenocarcinoma (2020)
  • Author(s): Masuzawa Keita、Asakura Takanori、Ikemura Shinnosuke、Yasuda Hiroyuki、Kawada Ichiro、Takaoka Sosuke、Hayashi Yuichiro、Nakajima Takeshi、Arai Masami、Fukunaga Koichi、Soejima Kenzo
  • Journal Title: JCO Precision Oncology Volume: 4 Pages: 74-78
  • DOI: 10.1200/po.19.00156
  • Peer Reviewed
• [Journal Article] Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study. (2019)
  • Author(s): Uwamino Y, Nishimura T, Sato Y, Tamizu E, Asakura T, Uno S, Mori M, Fujiwara H, Ishii M, Kawabe H, Murata M, Hasegawa N.
  • Journal Title: BMC Infectious Diseases Volume: 19(1) Pages: 1055-1055
  • DOI: 10.1186/s12879-019-4668-x
  • Peer Reviewed / Open Access
• [Journal Article] Airway M Cells Arise in the Lower Airway Due to RANKL Signaling and Reside in the Bronchiolar Epithelium Associated With iBALT in Murine Models of Respiratory Disease (2019)
  • Author(s): Kimura Shunsuke、Mutoh Mami、Hisamoto Meri、Saito Hikaru、Takahashi Shun、Asakura Takanori、Ishii Makoto、Nakamura Yutaka、Iida Junichiro、Hase Koji、Iwanaga Toshihiko
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 1323-1323
  • DOI: 10.3389/fimmu.2019.01323
  • Peer Reviewed / Open Access
• [Journal Article] Pneumothorax associated with giant bullous emphysema and mediastinum deviation (2019)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Ochi Junichi、Saito Fumitake
  • Journal Title: BMJ Case Reports Volume: 12
  • DOI: 10.1136/bcr-2019-230353
  • Peer Reviewed
• [Journal Article] Placental transmogrification of the lung masquerading as difficult-to-treat pneumonia (2019)
  • Author(s): Horiuchi K、Asakura T、Sakaguchi S、Saito F、Yamamoto J
  • Journal Title: QJM: An International Journal of Medicine Volume: 13 Pages: 213-214
  • DOI: 10.1093/qjmed/hcz153
  • Peer Reviewed / Open Access
• [Journal Article] Successful osimertinib treatment in a patient who exhibited intramedullary spinal cord metastases of lung adenocarcinoma with an acquired EGFR T790M mutation (2019)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Sakaguchi Shinji、Saito Fumitake
  • Journal Title: BMJ Case Reports Volume: 12
  • DOI: 10.1136/bcr-2019-229310
  • Peer Reviewed
• [Journal Article] Sitafloxacin-containing Regimen for the Treatment of Refractory Mycobacterium avium complex Lung Disease (2019)
  • Author(s): Asakura T, Suzuki S, Fukano H, Okamori S, Kusumoto T, Uwamino Y, Ogawa T, Matsuo So, Shunsuke Uno, Ho Namkoong, Yoshida M, Kamata H, Ishii M, Nishimura T, Hoshino Y, Hasegawa N.
  • Journal Title: Open Forum Infectious Diseases Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic values of the Berlin definition criteria, blood lactate level, and fibroproliferative changes on high-resolution computed tomography in ARDS patients (2019)
  • Author(s): Kamo Tetsuro、Tasaka Sadatomo、Suzuki Takeshi、Asakura Takanori、Suzuki Shoji、Yagi Kazuma、Namkoong Ho、Ishii Makoto、Morisaki Hiroshi、Betsuyaku Tomoko
  • Journal Title: BMC Pulmonary Medicine Volume: 19 Pages: 37-37
  • DOI: 10.1186/s12890-019-0803-0
  • Peer Reviewed / Open Access
• [Journal Article] Development of lung cancer in patients with nontuberculous mycobacterial lung disease (2019)
  • Author(s): Kusumoto Tatsuya、Asakura Takanori、Suzuki Shoji、Okamori Satoshi、Namkoong Ho、Fujiwara Hiroshi、Yagi Kazuma、Kamata Hirofumi、Ishii Makoto、Betsuyaku Tomoko、Hasegawa Naoki
  • Journal Title: Respiratory Investigation Volume: 57 Pages: 157-164
  • DOI: 10.1016/j.resinv.2018.11.004
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of intermittent maintenance therapy after successful treatment of Mycobacterium avium complex lung disease (2019)
  • Author(s): Asakura Takanori、Nakagawa Taku、Suzuki Shoji、Namkoong Ho、Morimoto Kozo、Ishii Makoto、Kurashima Atsuyuki、Betsuyaku Tomoko、Ogawa Kenji、Hasegawa Naoki
  • Journal Title: Journal of Infection and Chemotherapy Volume: 25 Pages: 218-221
  • DOI: 10.1016/j.jiac.2018.07.021
  • Peer Reviewed / Open Access
• [Journal Article] Adenovirus type 5 community-acquired pneumonia in an immunocompetent patient (2019)
  • Author(s): Masaki Katsunori、Asakura Takanori、Sakurai Kaori、Ohkusu Kiyofumi
  • Journal Title: BMJ Case Reports Volume: 12
  • DOI: 10.1136/bcr-2018-228914
  • Peer Reviewed
• [Journal Article] Rhabdomyolysis diagnosed in an elderly woman with dementia upon examination after a wandering episode (2019)
  • Author(s): Horiuchi K, Asakura T, Ikeda N.
  • Journal Title: Geriatrics & Gerontology International Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Disseminated histoplasmosis from a calcified lung nodule after long-term corticosteroid therapy in an elderly Japanese patient (2019)
  • Author(s): Kobayashi Keigo、Asakura Takanori、Kawada Ichiro、Hasegawa Hanako、Chubachi Shotaro、Ohara Kentaro、Kuramoto Junko、Sugiura Hiroaki、Fujishima Seitaro、Iwata Satoshi、Umeyama Takashi、Katano Harutaka、Uwamino Yoshifumi、Miyazaki Yoshitsugu、Kamei Katsuhiko、Hasegawa Naoki、Betsuyaku Tomoko
  • Journal Title: Medicine Volume: 98
  • DOI: 10.1097/md.0000000000015264
  • Peer Reviewed / Open Access
• [Journal Article] Bilateral chylothorax associated with osteophytes in an elderly patient (2019)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Sakaguchi Shinji、Saito Fumitake
  • Journal Title: BMJ Case Reports Volume: 12
  • DOI: 10.1136/bcr-2019-229473
  • Peer Reviewed
• [Journal Article] Infectious tenosynovitis of the long head of the biceps caused by methicillin-resistant Staphylococcus aureus in a patient with diabetes and small cell lung cancer (2019)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Bessho Yuki、Saito Fumitake
  • Journal Title: BMJ Case Reports Volume: 12
  • DOI: 10.1136/bcr-2018-229040
  • Peer Reviewed
• [Journal Article] Superior Vena Cava Syndrome (2019)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Saito Fumitake
  • Journal Title: QJM: An International Journal of Medicine Volume: なし
  • DOI: 10.1093/qjmed/hcz055
  • Peer Reviewed / Open Access
• [Journal Article] Black pleural effusion caused by pancreatic pseudocyst rupture (2019)
  • Author(s): Ishigaki Sho、Kuwae Misato、Ishii Makoto、Asakura Takanori、Ueda Soichiro、Betsuyaku Tomoko
  • Journal Title: Clinical Case Reports Volume: 7 Pages: 385-386
  • DOI: 10.1002/ccr3.1994
  • Peer Reviewed / Open Access
• [Journal Article] First report of hepatobiliary Mycobacterium avium infection developing obstructive jaundice in a patient with neutralizing anti?interferon-gamma autoantibodies (2019)
  • Author(s): Namkoong H.、Asakura T.、Ishii M.、Yoda S.、Masaki K.、Sakagami T.、Iwasaki E.、Yamagishi Y.、Kanai T.、Betsuyaku T.、Hasegawa N.
  • Journal Title: New Microbes and New Infections Volume: 27 Pages: 4-6
  • DOI: 10.1016/j.nmni.2018.10.001
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative assessment of erector spinae muscles in patients with Mycobacterium avium complex lung disease (2018)
  • Author(s): Asakura Takanori、Yamada Yoshitake、Suzuki Shoji、Namkoong Ho、Okamori Satoshi、Kusumoto Tatsuya、Niijima Yuki、Ozaki Akihiko、Hashimoto Masahiro、Yagi Kazuma、Kamata Hirofumi、Funatsu Yohei、Ishii Makoto、Jinzaki Masahiro、Betsuyaku Tomoko、Hasegawa Naoki
  • Journal Title: Respiratory Medicine Volume: 145 Pages: 66-72
  • DOI: 10.1016/j.rmed.2018.10.023
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. (2018)
  • Author(s): Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Yagi K, Komiya T, Hashimoto T, Okamori S, Kamata H, Tasaka S, Kihara A, Hegab AE, Hasegawa N, Betsuyaku T. S
  • Journal Title: Mucosal Immunology Volume: 11(6) Pages: 1606-1620
  • DOI: 10.1038/s41385-018-0077-5
  • Peer Reviewed
• [Journal Article] Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease. (2018)
  • Author(s): Yagi K, Asakura T, Namkoong H, Suzuki S, Asami T, Okamori S, Kusumoto T, Funatsu Y, Kamata H, Nishimura T, Ishii M, Betsuyaku T, Hasegawa N.
  • Journal Title: BMC Pulmonary Medicine Volume: 18(1) Pages: 114-114
  • DOI: 10.1186/s12890-018-0686-5
  • Peer Reviewed / Open Access
• [Journal Article] Health-related QOL of elderly patients with pulmonary M. avium complex disease in a university hospital (2018)
  • Author(s): Asakura T.、Ishii M.、Ishii K.、Suzuki S.、Namkoong H.、Okamori S.、Kamata H.、Yagi K.、Funatsu Y.、Betsuyaku T.、Hasegawa N.
  • Journal Title: The International Journal of Tuberculosis and Lung Disease Volume: 22 Pages: 695-703
  • DOI: 10.5588/ijtld.17.0433
  • Peer Reviewed / Open Access
• [Journal Article] Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease: A cross-sectional study (2018)
  • Author(s): Suzuki Shoji、Asakura Takanori、Namkoong Ho、Okamori Satoshi、Yagi Kazuma、Kamata Hirofumi、Uwamino Yoshifumi、Funatsu Yohei、Nakano Yasushi、Nishimura Tomoyasu、Ishii Makoto、Ebihara Tamotsu、Betsuyaku Tomoko、Hasegawa Naoki
  • Journal Title: Respir Med. Volume: 138 Pages: 1-6
  • DOI: 10.1016/j.rmed.2018.03.013
  • Peer Reviewed
• [Journal Article] Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. (2018)
  • Author(s): Namkoong H1,2, Ishii M1, Fujii H3, Yagi K1, Asami T1, Asakura T1, Suzuki S1, Hegab AE1, Kamata H1, Tasaka S1, Atarashi K4, Nakamoto N5, Iwata S6,7, Honda K4, Kanai T5, Hasegawa N6, Koyasu S4,8, Betsuyaku T1.
  • Journal Title: PLoS Pathog. Volume: 14(4)
  • DOI: 10.1371/journal.ppat.1006955
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: a case report (2018)
  • Author(s): Kobayashi Keigo、Asakura Takanori、Ishii Makoto、Ueda Soichiro、Irie Hidehiro、Ozawa Hiroyuki、Saitoh Kohei、Kurihara Isao、Itoh Hiroshi、Betsuyaku Tomoko
  • Journal Title: BMC Pulmonary Medicine Volume: 18 Pages: 142-142
  • DOI: 10.1186/s12890-018-0710-9
  • Peer Reviewed / Open Access
• [Journal Article] Lung cancer masquerading as fungus-associated mucoid impaction (2018)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Sakaguchi Shinji、Saito Fumitake
  • Journal Title: BMJ Case Reports Volume: 11
  • DOI: 10.1136/bcr-2018-227470
  • Peer Reviewed
• [Journal Article] Recurrence of allergic bronchopulmonary aspergillosis after adjunctive surgery for aspergilloma: a case report with long-term follow-up (2018)
  • Author(s): Horiuchi Kohei、Asakura Takanori、Hasegawa Naoki、Saito Fumitake
  • Journal Title: BMC Pulmonary Medicine Volume: 18 Pages: 185-185
  • DOI: 10.1186/s12890-018-0743-0
  • Peer Reviewed / Open Access
• [Journal Article] Perfusion Defect?Concordant Progression of Unilateral Refractory Pulmonary Mycobacterium avium Complex Disease (2018)
  • Author(s): Asakura Takanori、Yamada Yoshitake、Ishii Makoto、Ebisudani Toshiki、Ueda Soichiro、Betsuyaku Tomoko、Hasegawa Naoki
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 198 Pages: 803-804
  • DOI: 10.1164/rccm.201801-0173im
  • Peer Reviewed / Open Access
• [Journal Article] Development of Necrotizing Myopathy Following Interstitial Lung Disease with Anti-signal Recognition Particle Antibody (2018)
  • Author(s): Kusumoto T, Okamori S, Masuzawa K, Asakura T, Nishina N, Chubachi S, Naoki K, Fukunaga K, Betsuyaku T.
  • Journal Title: Intern. Med. Volume: in press Issue: 14 Pages: 2045-2049
  • DOI: 10.2169/internalmedicine.0303-17
  • NAID: 130006405652
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肺切除術を施行した肺非結核性抗酸菌(NTM)症の長期予後の検討 (2018)
  • Author(s): 朝倉 崇徳、早川 信崇、長谷川 直樹、南宮 湖、竹内 健、鈴木 翔二、石井 誠、別役 智子、阿部 能明、大内 基史
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 肺Mycobacterium aviumcomplex(MAC)症における抗重力筋評価の意義 (2018)
  • Author(s): 朝倉 崇徳、山田 祥岳、鈴木 翔二、南宮 湖、岡森 慧、楠本 竜也、新島 友輝、八木 一馬、鎌田 浩史、舩津 洋平、石井 誠、陣崎 雅弘、別役 智子、長谷川 直樹
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 肺Mycobacterium avium complex症に対する治療成功後の間欠的維持療法の効果と安全性に関する検討（多施設後ろ向き観察研究） (2018)
  • Author(s): 朝倉 崇徳、中川 拓、南宮 湖、鈴木 翔二、森本 耕三、石井 誠、倉島 篤行、小川 賢二、長谷川 直樹
  • Organizer: 第93回日本結核病学会総会
• [Presentation] 肺Mycobacterium avium complex (MAC)症に対するフルオロキノロン系抗菌薬 の位置付け (2018)
  • Author(s): 朝倉 崇徳、長谷川直樹
  • Organizer: 第93回日本結核病学会総会
• [Presentation] S1P受容体修飾薬はリンパ球減少とCD11b+Gr-1+細胞増加を誘導し肺気腫の進展を改善する (2018)
  • Author(s): 朝倉 崇徳
  • Organizer: 第3回Clinical Immunology/Inflammation Seminar
• [Presentation] S1P受容体修飾薬はリンパ球減少とCD11b+Gr-1+細胞増加を誘導し肺気腫の進展を改善する (2018)
  • Author(s): 朝倉 崇徳
  • Organizer: 信濃町Respiratory Forum 2018
• [Presentation] 肺Mycobacterium aviumcomplex(MAC)症における抗重力筋評価の意義 (2018)
  • Author(s): 朝倉 崇徳
  • Organizer: 第49回結核・非定型抗酸菌症治療研究会
• [Presentation] Sphingosine-1-phosphate Receptor Modulation Expands CD11b+Gr-1+ Cells and Inhibits Lymphocyte Infiltration to Ameliorate Murine Pulmonary Emphysema (2018)
  • Author(s): Asakura Takanori
  • Organizer: The 47th Annual Meeting of Japan Society for Immunology
• [Presentation] Quantitative Assessment of Erector Spinae Muscles in Patients with Mycobacterium Avium Complex Lung Disease: Relationship of Disease Severity and Prognosis (2018)
  • Author(s): Asakura T, Suzuki S, Okamori S, Kusumoto T, Namkoong H, Yagi K, Kamata H, Funatsu Y, Ishii M, Betsuyaku T, Hasegawa N
  • Organizer: ATS International Conference
  • Int'l Joint Research
• [Presentation] Clinical Utility of Serum Anti-glycopeptidolipid-core IgA Antibody in Patients Newly Diagnosed with Mycobacterium avium complex Lung Disease (2018)
  • Author(s): Asakura Takanori
  • Organizer: World Bronchiectasis Conference. 2018
  • Int'l Joint Research