Caspase-1-independent roles for inflammasome-forming proteins in bacterial infections

• Project/Area Number: 26460523
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Kanazawa University
• Principal Investigator: Tsuchiya Kohsuke 金沢大学, がん進展制御研究所, 助教 (50437216)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺炎球菌 / リステリア / インフラマソーム / NLRP3 / ASC / STAT6 / IL-18 / IL-10 / 自然免疫 / 感染防御 / AIM2 / 気道粘膜

Outline of Final Research Achievements

The aim of this study is to elucidate the roles for inflammasomes in infection with L. monocytogenes and S. pneumoniae, for the purpose of understanding pathological mechanism mediated by host-pathogen interactions. We found that the inflammasome adaptor ASC exacerbates lethal listeriosis by mediating IL-18 production, which leads to NK cell-dependent production of the immunosuppressive cytokine IL-10. It was also found that during pneumococcal pneumoniae, ASC sustains STAT6 activation in airway epithelial cells in an inflammasome-independent manner, thereby inhibiting the down-regulation of mucosal defense genes contributing to host defense against the pathogen. In addition, we reported that pneumolysin, a virulence factor of S. pneumoniae, plays a critical role in the production of IL-1α, which has been demonstrated as a mediator of lung inflammation, in response to this bacterium. The IL-1α production was dependent on calcium ions influx and calpain, but not the inflammasome.

Research Products

• [Int'l Joint Research] 西南大学(中国)
• [Journal Article] Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae. (2017)
  • Author(s): Fang R, Wu R, Du H, Jin M, Liu Y, Lei G, Jiang B, Lei Z, Peng Y, Nie K, Tsuchiya K.
  • Journal Title: Infect Immun. Volume: 85 Issue: 9
  • DOI: 10.1128/iai.00201-17
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation (2016)
  • Author(s): Zhang P, Tsuchiya K, Kinoshita T, Kushiyama H, Suidasari S, Hatakeyama M, Imura H, Kato N, Suda T.
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 47 Pages: 24517-24527
  • DOI: 10.1074/jbc.m116.743815
  • NAID: 120005983002
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A human pathogenic bacterial infection model using the two-spotted cricket, Gryllus bimaculatus (2016)
  • Author(s): Kochi, Y., Miyashita, A., Tsuchiya, K., Mitsuyama, M., Sekimizu, K., and Kaito, C.
  • Journal Title: FEMS Microbiol Lett Volume: 363 Issue: 15 Pages: fnw163-fnw163
  • DOI: 10.1093/femsle/fnw163
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serum syndecan-4 as a possible biomarker in patients with acute pneumonia (2015)
  • Author(s): Nikaido T, Tanino Y, Wang X, Sato S, Misa K, Fukuhara N, Sato Y, Fukuhara A, Uematsu M, Suzuki Y, Kojima T, Tanino M, Endo Y, Tsuchiya K, Kawamura I, Frevert C, Munakata M
  • Journal Title: J Infect Dis Volume: 212 Issue: 9 Pages: 1500-1508
  • DOI: 10.1093/infdis/jiv234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inactivation of the MAPK signaling pathway by Listeria monocytogenes infection promotes trophoblast giant cell death. (2015)
  • Author(s): Hashino M, Tachibana M, Nishida T, Hara H, Tsuchiya K, Mitsuyama M, Watanabe K, Shimizu T, Watarai M.
  • Journal Title: Front Microbiol Volume: 6 Pages: 1145-1145
  • DOI: 10.3389/fmicb.2015.01145
  • NAID: 120005947001
  • Peer Reviewed / Open Access
• [Journal Article] The adaptor ASC exacerbates lethal Listeria monocytogenes infection by mediating IL-18 production in an inflammasome-dependent and -independent manner. (2014)
  • Author(s): Tsuchiya K, Hara H, Fang R, Hernandez-Cuellar E, Sakai S, Daim S, Chen X, Dewamitta SR, Qu H, Mitsuyama M, Kawamura I.
  • Journal Title: European Journal of Immunology Volume: 44 Issue: 12 Pages: 3696-3707
  • DOI: 10.1002/eji.201444673
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Type I interferon signaling regulates the activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection. (2014)
  • Author(s): Fang R, Hara H, Sakai S, Hernandez-Cuellar E, Mitsuyama M, Kawamura I, Tsuchiya K.
  • Journal Title: Infect Immun. Volume: 82 Issue: 6 Pages: 2312-2317
  • DOI: 10.1128/iai.01572-14
  • Peer Reviewed
• [Presentation] Caspase-1 serves as an apoptosis-initiating caspase in the absence of Gasdermin D (GSDMD). (2017)
  • Author(s): Kohsuke Tsuchiya, Mahib Muhammad Mamunur Rashid, Takashi Suda
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS2017)
  • Int'l Joint Research
• [Presentation] シンポジウム「がん・免疫 -研究と臨床の最前線-」Caspase-1 依存的細胞死の分子機序と生理的役割 (2017)
  • Author(s): 土屋晃介
  • Organizer: 日本薬学会・北陸支部第 129 回例会
  • Invited
• [Presentation] Caspase-1 serves as an apoptosis-initiating caspase in the absence of Gasdermin D (GSDMD). (2017)
  • Author(s): Kohsuke Tsuchiya, Nakajima Shinsuke, and Takashi Suda
  • Organizer: 第 46回日本免疫学会学術集会
• [Presentation] A role for the redox master regulator Nrf2 in host defense against Listeria monocytogenes infection (2016)
  • Author(s): 土屋晃介（筆頭演者）
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄県宜野湾市
  • Year and Date: 2016-12-07
• [Presentation] Involvement of the redox master regulator Nrf2 in host defense against Listeria monocytogenes infection (2016)
  • Author(s): 土屋晃介（筆頭演者）
  • Organizer: 中国免疫学会第十一届全国免疫学学術大会
  • Place of Presentation: 中華人民共和国安徽省
  • Year and Date: 2016-11-07
• [Presentation] 細菌感染におけるインフラマソーム構成タンパクの新たな防御的役割 (2015)
  • Author(s): 土屋晃介（筆頭演者）、他
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 岐阜県・岐阜市
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] NLRP3 and ASC contribute to host defense against pneumococcal pneumonia in an inflammasome-independent manner (2014)
  • Author(s): 土屋晃介（筆頭演者）、他
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都府・京都市
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] インフラマソーム構成タンパクによる気道自然免疫の恒常性維持と肺炎球菌への宿主防御機序 (2014)
  • Author(s): 土屋晃介（筆頭演者）、他
  • Organizer: 第67回日本細菌学会関西支部総会
  • Place of Presentation: 兵庫県・西宮市
  • Year and Date: 2014-11-22
• [Presentation] 自然免疫機構による細胞内の監視と細胞内寄生菌の感染戦略 (2014)
  • Author(s): 土屋晃介（筆頭演者）、他
  • Organizer: 第25回日本生体防御学会学術総会
  • Place of Presentation: 宮城県・仙台市
  • Year and Date: 2014-07-09 – 2014-07-11
  • Invited
• [Book] パイロトーシスの分子機構と意義 (2016)
  • Author(s): 土屋晃介
  • Total Pages: 8
  • Publisher: 羊土社