title: Dendritic cell-based immunization ameliorates pulmonary infection with highly virulent Cryptococcus gattii.
abstract: Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection.
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Keigo
authors: K
authors: Ueno
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan ykinjo@niid.go.jp.
authors: Yuki
authors: Y
authors: Kinjo
authors: Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
authors: Yoichiro
authors: Y
authors: Okubo
authors: Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
authors: Kyoko
authors: K
authors: Aki
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Makoto
authors: M
authors: Urai
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan Department of Bacteriology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Yukihiro
authors: Y
authors: Kaneko
authors: Division of Molecular Biology, Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors: Kiminori
authors: K
authors: Shimizu
authors: Division of Clinical Research, Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors: Dan-Ni
authors: DN
authors: Wang
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Akiko
authors: A
authors: Okawara
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Takuya
authors: T
authors: Nara
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Kayo
authors: K
authors: Ohkouchi
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Yuki
authors: Y
authors: Mizuguchi
authors: Division of Molecular Biology, Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors: Susumu
authors: S
authors: Kawamoto
authors: Division of Clinical Research, Medical Mycology Research Center, Chiba University, Chiba, Japan Division of Control and Treatment of Infectious Diseases, Chiba University Hospital, Chiba, Japan.
authors: Katsuhiko
authors: K
authors: Kamei
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan Department of Infectious Diseases and Infection Control, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors: Hideaki
authors: H
authors: Ohno
authors: Division of Clinical Infectious Diseases, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
authors: Yoshihito
authors: Y
authors: Niki
authors: Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
authors: Kazutoshi
authors: K
authors: Shibuya
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Yoshitsugu
authors: Y
authors: Miyazaki
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D003453:Cryptococcosis / Q000276:immunology* / Q000517:prevention & control; D056285:Cryptococcus gattii / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D062607:Fungal Capsules / Q000235:genetics / Q000276:immunology*; D005657:Fungal Vaccines / Q000276:immunology*; D015726:Giant Cells / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014611:Vaccination
chemical_list: D005657:Fungal Vaccines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
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