NLRP3炎症复合体对人源巨噬细胞抵御马尔尼菲青霉感染的作用机制研究

Penicilliosis marneffei, which mostly occurred in HIV/AIDS individuals, is an infection caused by the dimorphic fungus Penicillium marneffei and it is an endemic fungal infection in South of China. As an intracellular pathogen, the pathways of Penicillium marneffei and the interaction with the host is particularly important in the study of the pathogenesis. In previous study, we have demonstrated the membrane bound receptors, which like TLR-2, TLR-4, TLR-9,of macrophage play an important role in the activation of innate immunity in fighting Penicillium marneffei infection. Toll-like receptors (TLRs) control synthesis of Pro-IL-1β,and IL-1β maturation and secretion depend on NLR-related protein 3 (NLRP3) inflammasome activation. Following the activation of caspase-1, the activation of NLRP3 inflammasome leading to the secretion of IL-1β and IL-18 can instruct the differentiation of Th1 and Th17 cells. Those responses may link to host defense by macrophage against Penicillium marneffei. This project tried to determine whether Penicillium marneffei infection could induce NLRP3 inflammasome formation throuth iv vitro macrophage system, and to determine how inflammasome activate and against Penicillium marneffei infection. Those findings would demonstrate the role for the NLRP3 inflammasome in innate immune response for host defense against Penicillium marneffei and find the underlying mechanism through activation of NLRP3 inflammasome. Then, the target therapeutic approach may have a potential role in the treatment for Penicilliosis marneffei in near future.

马尔尼菲青霉引起的马尔尼菲青霉病是中国南方HIV/AIDS患者中常见的严重侵袭性真菌病。作为胞内寄生菌，通过各种途径侵入宿主并抑制宿主的免疫反应是其致病关键。我们已证实该菌能上调小鼠巨噬细胞跨膜模式识别受体TLR-2、TLR-4、TLR-9等的表达；TLR可调控IL-1β前体Pro-IL-1β的合成，但IL-1β的成熟依赖NLRP3炎症复合体活化caspase-1，进一步诱导IL-18、IL-1β等分泌，进而调节免疫应答。我们推测巨噬细胞NLRP3炎症复合体在其抵御马尔尼菲青霉感染中起一定作用。本项目拟通过检测马尔尼菲青霉刺激后，人源巨噬细胞THP-1的NLRP3炎症复合体的形成情况及其对杀伤该菌的影响，获得NLRP3炎症复合体在巨噬细胞抵御马尔尼菲青霉感染中的可靠依据，同时阐明其被激活的相关通路，为研发疫苗和开发新的抗真菌药物作用靶点提供充分的科学依据。

马尔尼菲蓝状菌（曾用名：马尔尼菲青霉）引起的马尔尼菲青霉病是中国南方HIV/AIDS患者中常见的严重侵袭性真菌病。该菌侵入宿主途径及侵入后激活的免疫反应被认为是致病的关键，我们前期已证实该菌能上调小鼠巨噬细胞跨膜模式识别受体TLR-2等的表达，进而激活IL-1β前体Pro-IL-1β。我们通过检测马尔尼菲蓝状菌刺激后，人源巨噬细胞THP-1的NLRP3炎症复合体主要成分NLRP3、ASC蛋白的激活、其的激活对杀伤该菌的影响，证实IL-1β成熟依赖NLRP3炎症复合体的形成，通过活化caspase-1，进一步诱导IL-1β分泌，进而调节免疫应答。本项目获得NLRP3炎症复合体在巨噬细胞抵御马尔尼菲蓝状菌感染的作用的可靠依据，同时阐明其如何被激活而参与天然免疫应答.