Systemic studies of murine pulmonary cryptococcosis: Candidate virulence factors against cryptococci

• Project/Area Number: 26860774
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kanagawa Cancer Center Research Institute (2015-2016); Toho University (2014)
• Principal Investigator: Okubo Yoichiro 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), その他部局等, 医長 (40516267)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Cryptococcus gattii / Cryptococcus neoformans / DNAマイクロアレイ / 肉芽腫 / Pgk1 / 樹状細胞ワクチン / CD4 / PGK1 / ＣＤ４ / 肺胞 / クリプトコックス / 多核巨細胞 / 感染防御機構

Outline of Final Research Achievements

Cryptococcus gattii R265, which was responsible for the cryptococcosis outbreak on Vancouver Island, can cause life-threatening infectious diseases. However, putative mechanisms of its high virulence remain unclear.To elucidate factors affecting high virulence of this yeast, we conducted the systemic examinations using the lungs of the mice infected with C. gattii R265 and 5815 and C. neoformans H99. In addition, microarray assay with gene ontology analysis was also carried out.
Results showed that C. gattii R265 can easily proliferate in alveoli due to the poor cryptococcal yeast-cell recognition by macrophages and/or other antigen-presenting cells. Furthermore, microarray data suggested C. gattii R265 may have high adherence ability to the alveolar epithelium.
In conclusion, our investigations revealed that C. gattii R265 induces less macrophage response and severe structural alteration of the lungs. These characteristics may be candidates for virulence factor of this yeast.

Research Products

• [Journal Article] A linking bridge between histopathological analysis and molecular assay in microbiology (2017)
  • Author(s): Okubo Y
  • Journal Title: Malaysian Journal of Pathology Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure. (2016)
  • Author(s): Okubo Y, Motohashi O, Nakayama N, Nishimura K, Kasajima R, Miyagi Y, Shiozawa M, Yoshioka E, Suzuki M, Washimi K, Kawachi K, Nito M, Kameda Y, Yokose T.
  • Journal Title: Diagnostic Pathology Volume: 11 Issue: 1
  • DOI: 10.1186/s13000-016-0580-5
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Duodenal Rare Neuroendocrine Tumor: Clinicopathological Characteristics of Patients with Gangliocytic Paraganglioma. (2016)
  • Author(s): Okubo Y, Yokose T, Motohashi O, Miyagi Y, Yoshioka E, Suzuki M, Washimi K, Kawachi K, Nito M, Nemoto T, Shibuya K, Kameda Y.
  • Journal Title: Gastroenterology Research and Practice Volume: 5257312 Pages: 1-10
  • DOI: 10.1155/2016/5257312
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neuroendocrine Differentiation in Breast Cancer: Clinicopathological Significance of Bcl-2 Positive Solid Papillary Carcinoma. (2016)
  • Author(s): Okubo Y, Okubo T, Okubo Y, Ishiwatari T.
  • Journal Title: Case Reports in Medicine Volume: 9501410 Pages: 1-6
  • DOI: 10.1155/2016/9501410
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evasion of Innate Immune Responses by the Highly Virulent Cryptococcus gattii by Altering Capsule Glucuronoxylomannan Structure (2016)
  • Author(s): Urai M, Kaneko Y, Ueno K, Okubo Y, Aizawa T, Fukazawa H, Sugita T, Ohno H, Shibuya K, Kinjo Y and Miyazaki Y
  • Journal Title: Front Cell Infect Microbiol Volume: 5 Pages: 101-101
  • DOI: 10.3389/fcimb.2015.00101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histological study of chronic pulmonary aspergillosis (2015)
  • Author(s): Tochigi N, Ishiwatari T, Okubo Y, Ando T, Shinozaki M, Aki K, Gocho K, Hata Y, Murayama SY, Wakayama M, Nemoto T, Hori Y, Shibuya K
  • Journal Title: Diagn Pathol Volume: 10 Issue: 1 Pages: 153-153
  • DOI: 10.1186/s13000-015-0388-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A case of postoperative hepatic granuloma presumptively caused by surgical staples/clipping materials. (2015)
  • Author(s): Nihon-Yanagi Y, Ishiwatari T, Otsuka Y, Okubo Y, Tochigi N, Wakayama M, Nemoto T, Watanabe M, Kaneko H, Sumino Y, Shibuya K.
  • Journal Title: Diagnostic Pathology Volume: 10 Issue: 1 Pages: 1-5
  • DOI: 10.1186/s13000-015-0291-3
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan. (2015)
  • Author(s): Okubo Y, Nemoto T, Wakayama M, Tochigi N, Shinozaki M, Ishiwatari T, Aki K, Tsuchiya M, Aoyama H, Katsura K, Fujii T, Nishigami T, Yokose T, Ohkura Y, Shibuya K
  • Journal Title: BMC Cancer Volume: 15 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12885-015-1308-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of habitual exercise and dietary restriction on intrahepatic and periepididymal fat accumulation in Zucker fatty rats. (2015)
  • Author(s): Kurosaka Y, Shiroya Y, Yamauchi H, Kaneko T, Okubo Y, Shibuya K, Minato K.
  • Journal Title: BMC Research Notes Volume: 8 Issue: 1 Pages: 121-121
  • DOI: 10.1186/s13104-015-1063-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic analysis for single nucleotide polymorphisms (Asp299Gly and Thr399lle) in Japanese patients with invasive aspergillosis (2015)
  • Author(s): Aki K, Okubo Y, Nanjo H, Ishiwatari T, Nihonyanagi Y, Tochigi N, Wakayama M, Nemoto T, Fukutake K, Shinozaki M, Hori Y, Masuda H, Shibuya K
  • Journal Title: Japanese Journal of Infectious Diseases Volume: In press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tracheal leiomyoma resected with endobronchial electrocautery snare (2015)
  • Author(s): Nakamura Y, Hata Y, Koezuka S, Makino T, Otsuka H, Sato F, Sasamoto S, Okubo Y, Nemoto T, Shibuya K, Iyoda A
  • Journal Title: Journal of Bronchology and Interventional Pulmonology Volume: 22 Issue: 1 Pages: 90-93
  • DOI: 10.1097/lbr.0000000000000107
  • Peer Reviewed
• [Journal Article] 肺アスペルギルス症の病理学的考察 (2014)
  • Author(s): 栃木直文, 大久保陽一郎, 澁谷和俊
  • Journal Title: 呼吸器内科 Volume: 26 Pages: 22-26
  • Acknowledgement Compliant
• [Journal Article] Comparison between the location and the histomorphological/immunohistochemical characteristics of noninvasive neoplasms of the ampulla of Vater (2014)
  • Author(s): Yamamoto Y, Nemoto T, Okubo Y, Nihonyanagi Y, Ishiwatari T, Takuma K, Tochigi N, Okano N, Wakayama M, Igarashi Y, Shibuya K
  • Journal Title: Hum Pathol Volume: 45 Issue: 9 Pages: 1910-7
  • DOI: 10.1016/j.humpath.2014.05.013
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] クリプトコックス剖検例の病理組織学的解析 (2015)
  • Author(s): 石渡誉郎, 二本柳康博, 大久保陽一郎, 定本聡太, 小林純子, 江嶋梢, 栃木直文, 篠崎稔, 若山恵, 根本哲生, 澁谷和俊
  • Organizer: 第59回日本医真菌学会総会・学術集会
  • Place of Presentation: 札幌(北海道)
  • Year and Date: 2015-10-09
• [Presentation] クリプトコックス剖検例の病理組織学的解析 (2015)
  • Author(s): 石渡誉郎, 二本柳康宏, 大久保陽一郎, 栃木直文, 若山恵, 根本哲生, 澁谷和俊
  • Organizer: 第36回関東医真菌懇話会
  • Place of Presentation: 札幌(北海道)
  • Year and Date: 2015-06-27
• [Presentation] Histopathological study of murine pulmonary cryptococcosis: candidate virulence factors against Cryptococci (2015)
  • Author(s): Okubo Y, Ohno H, Ueno K, Aki K, Shinozaki M, Nihonyanagi Y, Ejima K, Ishiwatari T, Tochigi N, Mitsuda A, Wakayama M, Nemoto T, Hori Y, Kinjo Y, Miyazaki Y, Kamei K, Shibuya K
  • Organizer: 19th Congress of the International Society for Human and Animal Mycology
  • Place of Presentation: Melbourne(Australia)
  • Year and Date: 2015-05-04
  • Int'l Joint Research
• [Presentation] Identification of dimorphic yeast in FFPE tissue sections by in situ hybridization using PNA probes (2015)
  • Author(s): Okubo Y, Aki K, Shinozaki M, Nihonyanagi Y, Ejima K, Ishiwatari, T, Tochigi N, Mitsuda A, Wakayama M, Nemoto T, Hori Y, Shibuya k
  • Organizer: 19th Congress of the International Society for Human and Animal Mycology
  • Place of Presentation: Melbourne (Australia)
  • Year and Date: 2015-05-04
  • Int'l Joint Research
• [Presentation] Histopathological study of autopsy subjects with cryptococcosis (2015)
  • Author(s): Ishiwatari T, Nihonyanagi Y, Ejima K, Okubo Y, Tochigi N, Shinozaki M, Wakayama M, Nemoto T, Shibuya K
  • Organizer: 19th Congress of the International Society for Human and Animal Mycology
  • Place of Presentation: Melbourne(Australia)
  • Year and Date: 2015-05-04
  • Int'l Joint Research
• [Presentation] マウス肺を用いたクリプトコックス感染症に対する組織学的解析：感染防御機構の観点から (2015)
  • Author(s): 大久保陽一郎, 大野秀明, 上野圭吾, 石渡誉郎, 栃木直文, 若山恵, 根本哲生, 金城雄樹, 宮崎義継, 澁谷和俊
  • Organizer: 第104回日本病理学会総会 名古屋
  • Place of Presentation: 名古屋(愛知)
  • Year and Date: 2015-05-01
• [Presentation] 剖検例を用いたクリプトコックス症の病理学的解析 (2015)
  • Author(s): 石渡誉郎, 二本柳康博, 大久保陽一郎, 栃木直文, 若山恵, 根本哲生, 澁谷和俊
  • Organizer: 第104回日本病理学会総会 名古屋
  • Place of Presentation: 名古屋
  • Year and Date: 2015-05-01
• [Presentation] 高病原性cryptcoccus gattii の感染防衛に寄与する樹状細胞ワクチンの作用 (2014)
  • Author(s): 上野圭吾, 金城雄樹, 大久保陽一郎, 清水公徳, 金子幸弘, 浦井誠, 川本進, 亀井克彦, 大野秀明, 澁谷和俊, 宮﨑義継
  • Organizer: 第58回日本医真菌学会総会・学術集会
  • Place of Presentation: ワークピア横浜・横浜産貿ホール(神奈川)
  • Year and Date: 2014-11-02
• [Presentation] マクロファージの貪食を指標としたCryptococcus gattii感染病態の評価 (2014)
  • Author(s): 壇辻百合香, 大野秀明, 梅山隆, 上野圭吾, 大久保陽一郎, 田辺公一, 名木稔, 山越智, 金城雄樹, 杉田隆, 澁谷和俊, 宮﨑義継
  • Organizer: 第58回日本医真菌学会総会・学術集会
  • Place of Presentation: ワークピア横浜・横浜産貿ホール(神奈川)
  • Year and Date: 2014-11-02
• [Presentation] Cryptococcus gattii株における病原性発現機構の解明 (2014)
  • Author(s): 大久保陽一郎, 大野秀明, 安藝恭子, 篠崎稔, 石渡誉郎, 栃木直文, 若山恵, 根本哲生, 下平佳代子, 中山晴雄, 田辺公一, 山越智, 金子幸弘, 宮﨑義継, 亀井克彦, 澁谷和俊
  • Organizer: 第58回日本医真菌学会総会・学術集会
  • Place of Presentation: ワークピア横浜・横浜産貿ホール(神奈川)
  • Year and Date: 2014-11-01
• [Presentation] クリプトコックスの莢膜多糖による免疫回避機構の解析及びその制御法の開発 (2014)
  • Author(s): 金城雄樹, 上野圭吾, 浦井誠, 金子幸弘, 大久保陽一郎, 清水公徳, 大野秀明, 亀井克彦, 川本進, 澁谷和俊, 宮﨑義継
  • Organizer: 第58回日本医真菌学会総会・学術集会
  • Place of Presentation: ワークピア横浜・横浜産貿ホール(神奈川)
  • Year and Date: 2014-11-01
• [Presentation] 高病原性Cryptococcus gattiの感染防衛に寄与する樹状細胞ワクチン (2014)
  • Author(s): 上野圭吾, 金城雄樹, 大久保陽一郎, 浦井 誠, 金子幸弘, 大野秀明, 亀井克彦、澁谷和俊, 宮崎義継
  • Organizer: 第63回日本感染症学会東日本地方会総会学術集会 第61回日本化学療法学会東日本支部総会 合同学会
  • Place of Presentation: 東京ドームホテル (東京)
  • Year and Date: 2014-10-30