Study on the molecular pathogenesis of opportunistic fungal infectious diseases in AIDS patients

艾滋病患者机会性真菌感染性疾病的分子发病机制研究

• 批准号: 12670261
• 负责人: KAWAKAMI Kazuyoshi
• 金额: $ 1.54万
• 依托单位: University of the Ryukyus
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670261/
• 关键词: Fungal infection; Cryptococcus; Penicillium marneffei; Innate immunity; NKT cells; γδT cells; オステオポンチン; エイズ; 日和見真菌感染症; NK細胞; IFN-_γ; IL-18; IL-12; IFN-gamma

We have investigated the host defense mechanism against Cryptococcus neoformans infection using a mouse model to clarify the molecular mechanisms of opportunistic fungal infection complicated in AIDS. In this study, we evaluated the roles of innate immune lymphocytes, such as NK NKT and γδ T cells. NK and NKT cells accumulated in lung and regional lymphmode in a MCP-1-dependent manner after cryptococcal infection, while the accumulation of γδ T cells was not dependent of this chemokine. NKT cells were found to play an important role in the development of Th1-mediated host protection from this infection using mice genetically lacking Vα14 NKT cells. In contrast, γδ T cells were suggested to negatively regulate these responses, because the infection was improved in mice depleted of these cells by administration of ant-γδ TCR mAb. Further investigations are now under way. On the other hand, we also demonstrated in an in-vitro study using peripheral blood mononuclear cells the involvement of osteopontin in the IL-12-induced Th1 responses in infection with Penicillium marneffei, a major opportunistic fungal pathogen in AIDS patients in Southeast Asia. In the present study, we have approached the process reaching from innate to acquired immune responses during fungal infection, which may provide a basic implication in constructing the strategies for prevention and treatment against AIDS-related infection caused by these pathogens.

我们利用小鼠模型研究了宿主针对新型隐球菌感染的防御机制，以阐明艾滋病并发机会性真菌感染的分子机制。在这项研究中，我们评估了天然免疫淋巴细胞的作用，例如 NK NKT 和 γδ T 细胞。隐球菌感染后，NK和NKT细胞以MCP-1依赖性方式在肺和区域淋巴模式中积累，而γδT细胞的积累不依赖于这种趋化因子。使用遗传上缺乏 Vα14 NKT 细胞的小鼠发现 NKT 细胞在 Th1 介导的宿主免受这种感染的保护中发挥着重要作用。相比之下，γδ T 细胞被认为负向调节这些反应，因为通过给予 ant-γδ TCR mAb，这些细胞耗尽的小鼠的感染得到了改善。目前正在进行进一步调查。另一方面，我们还在一项使用外周血单核细胞的体外研究中证明了骨桥蛋白参与了马尔尼菲青霉菌感染中IL-12诱导的Th1反应，马尔尼菲青霉是东南亚艾滋病患者中的一种主要机会性真菌病原体。在本研究中，我们探讨了真菌感染过程中从先天免疫反应到获得性免疫反应的过程，这可能为构建针对这些病原体引起的艾滋病相关感染的预防和治疗策略提供基本启示。

项目成果

Kawakami, K.et al.: "Activation of Vα14+ Natural Killer T Cells by α-Galactosylceramide Results in the Development of Th1 Response and Local Host Resistance in Mice Infected with Cryptococcus neoformans"Infection and Immunigy. 69. 213-220 (2001)

Kawakami, K. 等人：“α-半乳糖神经酰胺激活 Vα14+ 自然杀伤 T 细胞导致感染新型隐球菌的小鼠产生 Th1 反应和局部宿主抵抗”，《感染和免疫学》69. 213-220 (2001)。

Kawakami, K. et al.: "Minimal contribution of Vα14 natural killer T cells to Th1 response and host resistance against mycobacterial infection in mice"Microbiology and Immunology. 46. 207-210 (2002)

Kawakami, K. 等人：“Vα14 自然杀伤 T 细胞对小鼠分枝杆菌感染的 Th1 反应和宿主抵抗力的最小贡献”微生物学和免疫学。 46. 207-210 (2002)。

Kawakami, K. et al.: "Anti-CD11b monoclonal antibody suppresses brain dissemination of cryptococcus neoformans in mice"Microbiology and Immunology. 46(3)(印刷中). (2002)

Kawakami, K. 等人：“抗 CD11b 单克隆抗体抑制小鼠新生隐球菌的脑传播”微生物学和免疫学 46(3)（出版中）。

Kawakami, K., Koguchi, Y., Qureshi, M. H., et al.: "NK cells eliminate Cryptococcus neoformans by potentiating the fungicidal activity of macrophages, rather than by directly killing them, upon stimulation with IL-12 and IL-18"Microbiol. Immunol.. 44. 104

Kawakami, K.、Koguchi, Y.、Qureshi, M. H. 等人：“NK 细胞在受到 IL-12 和 IL-18 刺激后，通过增强巨噬细胞的杀菌活性来消除新型隐球菌，而不是直接杀死它们”

Kawakami, K.: "Interleukin-18 and host defense against infectious pathogens"J. Immunotherapy. 25. S12 (2002)

Kawakami, K.：“Interleukin-18 和宿主对传染性病原体的防御”J.