Bellocchio Silvia, Montagnoli Claudia, Bozza Silvia, Gaziano Roberta, Rossi Giordano, Mambula Salamatu S, Vecchi Annunciata, Mantovani Alberto, Levitz Stuart M, Romani Luigina
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
J Immunol. 2004 Mar 1;172(5):3059-69. doi: 10.4049/jimmunol.172.5.3059.
In vitro studies have indicated the importance of Toll-like receptor (TLR) signaling in response to the fungal pathogens Candida albicans and Aspergillus fumigatus. However, the functional consequences of the complex interplay between fungal morphogenesis and TLR signaling in vivo remain largely undefined. In this study we evaluate the impact of the IL-1R/TLR/myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway on the innate and adaptive Th immunities to C. albicans and A. fumigatus in vivo. It was found that 1) the MyD88-dependent pathway is required for resistance to both fungi; 2) the involvement of the MyD88 adapter may occur through signaling by distinct members of the IL-1R/TLR superfamily, including IL-1R, TLR2, TLR4, and TLR9, with the proportional role of the individual receptors varying depending on fungal species, fungal morphotypes, and route of infection; 3) individual TLRs and IL-1R activate specialized antifungal effector functions on neutrophils, which correlates with susceptibility to infection; and 4) MyD88-dependent signaling on dendritic cells is crucial for priming antifungal Th1 responses. Thus, the finding that the innate and adaptive immunities to C. albicans and A. fumigatus require the coordinated action of distinct members of the IL-1R/TLR superfamily acting through MyD88 makes TLR manipulation amenable to the induction of host resistance to fungi.
体外研究表明，Toll样受体（TLR）信号传导在应对真菌病原体白色念珠菌和烟曲霉时具有重要作用。然而，真菌形态发生与TLR信号传导在体内复杂相互作用的功能后果仍 largely undefined。在本研究中，我们评估了白细胞介素-1受体（IL-1R）/TLR/髓样分化初级反应基因88（MyD88）依赖性信号通路对白色念珠菌和烟曲霉体内固有免疫和适应性Th免疫的影响。研究发现：1）MyD88依赖性通路是抵抗这两种真菌所必需的；2）MyD88衔接蛋白的参与可能通过IL-1R/TLR超家族的不同成员发出信号，包括IL-1R、TLR2、TLR4和TLR9，单个受体的比例作用因真菌种类、真菌形态型和感染途径而异；3）单个TLR和IL-1R激活中性粒细胞上的特异性抗真菌效应功能，这与感染易感性相关；4）树突状细胞上的MyD-88依赖性信号传导对于启动抗真菌Th1反应至关重要。因此，对白色念珠菌和烟曲霉的固有免疫和适应性免疫需要IL-1R/TLR超家族的不同成员通过MyD88协同作用这一发现，使得TLR操纵适合于诱导宿主对真菌的抵抗力。
