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

我们用小鼠模型研究了宿主对新生隐球菌感染的防御机制，以阐明艾滋病合并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，如NK NKT和γδT细胞的作用。隐球菌感染后，NK和NKT细胞以单核细胞趋化蛋白-1依赖的方式聚集在肺和区域淋巴中，而γδT细胞的聚集不依赖于这种趋化因子。利用遗传缺失Vα14NKT细胞的小鼠，发现NKT细胞在Th1介导的宿主保护中发挥重要作用。相反，γδT细胞被认为可以负向调节这些反应，因为通过注射Ant-γδTCRmAb，这些细胞耗尽的小鼠的感染得到了改善。进一步的调查目前正在进行中。另一方面，我们还在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IL-12诱导的马尔尼菲青霉菌感染的Th1反应。马尔尼菲青霉菌是东南亚艾滋病患者的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，这可能为制定预防和治疗这些病原体引起的艾滋病相关感染的策略提供基本的指导意义。

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.