Analysis of CARD9 function in pulmonary mycobacterial infection

• Project/Area Number: 20K16285
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Fukuoka Dental College (2021-2022); Osaka University (2020)
• Principal Investigator: Toyonaga Kenji 福岡歯科大学, 口腔歯学部, 助教 (90791567)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 宿主防御 / 抗酸菌感染 / Th1応答 / 自然免疫 / 抗酸菌

Outline of Research at the Start

マクロファージや樹状細胞に発現しているC型レクチン受容体などのシグナル伝達に必須の役割を担うCARD9の欠損マウスは、結核菌感染に対する抵抗性が著しく減弱することが報告されている。CARD9は特に、感染初期の宿主防御に重要であると考えられているものの、寄与する免疫応答の詳細は不明である。申請者は、これまでの解析から、感染局所への炎症性単球やNK細胞浸潤にCARD9が重要な役割を担っていることを見出した。そこで本研究では、抗酸菌感染に対する初期防御応答において、炎症性単球とNK細胞のどちらが重要であるかを明らかにし、この経路におけるCARD9の役割解明を目的とする。

Outline of Final Research Achievements

CARD9 is known to play an essential role in innate immune signaling via C-type lectin receptors. CARD9-deficient mice were shown to be highly susceptible to Mycobacterium tuberculosis. In CARD9-deficient mice, the antigen-specific T cell response after infection is comparable to that of wild-type (WT) mice, and it is thus considered that CARD9 deficiency affects innate immunity rather than acquired T cell responses during infection. However, the contribution of CARD9 to early mycobacterial infection is poorly understood.
To clarify the role of CARD9 in the early stages of mycobacterial infection, CARD9-deficient mice were infected intratracheally with M. bovis BCG. We found that bacterial loads in the lungs were comparable between WT and CARD9-deficient mice 7 and 21 days after infection. These results suggest that CARD9 might not contribute to the elimination of bacteria in the early stages of pulmonary M. bovis BCG infection.

Academic Significance and Societal Importance of the Research Achievements

マウス感染モデルを用いた解析や、様々な疫学的知見から、CARD9を介した自然免疫活性化は、病原体感染に対する重要な宿主防御機構の一つと考えられ、CARD9経路を増強させることによって、病原体の排除を促す試みもいくつか行われている。このことから、本研究において見出した知見は、CARD9を介した免疫活性化機構の解明だけでなく、関連する感染性疾患の新規治療法開発にも繋がる可能性がある。

Research Products

• [Journal Article] Pathobiont-responsive Th17 cells in gut-mouth axis provoke inflammatory oral disease and are modulated by intestinal microbiome (2022)
  • Author(s): Nagao J, Kishikawa S, Tanaka H, Toyonaga K, Narita Y, Negoro-Yasumatsu K, Tasaki S, Arita-Morioka K, Nakayama J, Tanaka Y
  • Journal Title: Cell Rep Volume: 40 Issue: 10 Pages: 111314-111314
  • DOI: 10.1016/j.celrep.2022.111314
  • Peer Reviewed / Open Access
• [Journal Article] TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation. (2021)
  • Author(s): Iizasa, E., Chuma, Y., Uematsu, T., Kubota, M., Kawaguchi, H., Umemura, M., Toyonaga, K., Kiyohara, H., Yano, I., Colonna, M., Sugita, M., Matsuzaki, G., Yamasaki, S., Yoshida, H., Hara, H.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2299-2314
  • DOI: 10.1038/s41467-021-22620-3
  • NAID: 120007170570
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] C型レクチン受容体はHelicobacter pyloriの代謝産物を認識して胃炎の増悪に寄与する (2021)
  • Author(s): 豊永憲司、山﨑晶
  • Journal Title: 臨床免疫・アレルギー科 Volume: 76 (1) Pages: 84-92
  • NAID: 40022634563
• [Journal Article] Helicobacter metabolites exacerbate gastritis through C-type lectin receptors. (2021)
  • Author(s): Nagata M, Toyonaga K, Ishikawa E, Haji S, Okahashi N, Takahashi M, Izumi Y, Imamura A, Takato K, Ishida H, Nagai S, Illarionov P, Stocker B L, Timmer M S M, Smith D G M, Williams S J, Bamba T, Miyamoto T, Arita M, Appelmelk B J, Yamasaki S*.
  • Journal Title: J. Exp. Med. Volume: 218(1) Issue: 1
  • DOI: 10.1084/jem.20200815
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recognition of Mycobacteria by Dendritic Cell Immunoactivating Receptor (2020)
  • Author(s): Toyonaga K, Yamasaki S.
  • Journal Title: Current topics in microbiology and immunology Volume: 429 Pages: 103-115
  • DOI: 10.1007/82_2020_203
  • ISBN: 9783030622367, 9783030622374
  • Peer Reviewed
• [Presentation] Analysis of immune responses in a murine oral candidiasis model (2022)
  • Author(s): Kenji Toyonaga、Emi Kaji、Jun-ichi Nagao、Sonoko Tasaki、Sari Kishikawa、Kanae Negoro-Yasumatsu、Yoshihiko Tanaka
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Investigation of Th17-cell mediated immune response against the pathogenic fungus Candida albicans (2022)
  • Author(s): Emi Kaji、Kenji Toyonaga、Sonoko Tasaki、Jun-ichi Nagao、Sari Kishikawa、Mizuko Ikeda、Yosihiko Tanaka
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Development of periodontitis mediated by T-cell immune response against periodontal bacteria (2022)
  • Author(s): Jun-ichi Nagao、Sari Kishikawa、Kenji Toyonaga、Emi Kaji、Kanae Negoro-Yasumatsu、Sonoko Tasaki、Yoshihiko Tanaka
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Immunological analysis of periodontal disease-induced cognitive disorders in mice (2022)
  • Author(s): Sari Kishikawa、Jun-ichi Nagao、Kenji Toyonaga、Emi Kaji、Kanae Negoro-Yasumatsu、Sonoko Tasaki、Yoshihiko Tanaka
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Analysis of immune responses to Candida albicans in a murine oral infection model (2022)
  • Author(s): Toyonaga K、Nagao J、Mizukami K、Tasaki S、Kishikawa S、Kaji E、Negoro K、Tanaka Y
  • Organizer: The 64th Annual Meeting of Japanese Association for Oral Biology
• [Presentation] Investigation of immunological systems regulating the pathogenesis of periodontitis (2022)
  • Author(s): Nagao J、Kishikawa S、Toyonaga K、Kaji E、Negoro-Yasumatsu K、Tasaki S、Tanaka Y
  • Organizer: The 64th Annual Meeting of Japanese Association for Oral Biology
• [Presentation] Neuroimmunological analysis using the mouse model of periodontal disease (2022)
  • Author(s): Kishikawa S、Nagao J、Toyonaga K、Kaji E、Negoro K、Tasaki S、Tanaka Y
  • Organizer: The 64th Annual Meeting of Japanese Association for Oral Biology
• [Presentation] Exploration of antigens from the pathogenic fungus Candida albicans that regulate the pathogenesis of oral candidiasis (2022)
  • Author(s): Kaji E、Toyonaga K、Tasaki S、Nagao J、Kisikawa S、Tanaka Y
  • Organizer: The 64th Annual Meeting of Japanese Association for Oral Biology
• [Presentation] Analysis of host responses against secondary infection of Candida albicans (2022)
  • Author(s): Mizukami K、Toyonaga K、Tanaka Y
  • Organizer: The 64th Annual Meeting of Japanese Association for Oral Biology
• [Presentation] Analysis of Card9 function in pulmonary mycobacterial infection (2022)
  • Author(s): Kenji Toyonaga, Masayuki Umemura, Goro Matsuzaki, Hiromitsu Hara, Yoshihiko Tanaka, and Sho Yamasaki
  • Organizer: 第95回日本細菌学会総会
• [Presentation] 口腔内細菌脂質成分の自然免疫活性化能の解析 (2021)
  • Author(s): 豊永憲司、永尾潤一、岸川咲吏、田中芳彦
  • Organizer: 第63回歯科基礎医学会学術大会
• [Presentation] 抗酸菌の糖脂質はどのようにして宿主免疫を活性化するのか (2021)
  • Author(s): 豊永憲司
  • Organizer: 第96回日本結核・非結核性抗酸菌症学会総会・学術講演会
  • Invited
• [Patent(Industrial Property Rights)] ヘリコバクター属菌に起因する疾患または状態を処置する方法、およびその利用 (2020)
  • Inventor(s): 山崎 晶、豊永 憲司
  • Industrial Property Rights Holder: 山崎 晶、豊永 憲司
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-157742
  • Filing Date: 2020