Genster Ninette, Præstekjær Cramer Elisabeth, Rosbjerg Anne, Pilely Katrine, Cowland Jack Bernard, Garred Peter
Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Innate Immun. 2016;8(6):579-588. doi: 10.1159/000447714. Epub 2016 Jul 29.
Aspergillus fumigatus is an opportunistic fungal pathogen that causes severe invasive infections in immunocompromised patients. Innate immunity plays a major role in protection against A. fumigatus. The ficolins are a family of soluble pattern recognition receptors that are capable of activating the lectin pathway of complement. Previous in vitro studies reported that ficolins bind to A. fumigatus, but their part in host defense against fungal infections in vivo is unknown. In this study, we used ficolin-deficient mice to investigate the role of ficolins during lung infection with A. fumigatus. Ficolin knockout mice showed significantly higher fungal loads in the lungs 24 h postinfection compared to wild-type mice. The delayed clearance of A. fumigatus in ficolin knockout mice could not be attributed to a compromised recruitment of inflammatory cells. However, it was revealed that ficolin knockout mice exhibited a decreased production of proinflammatory cytokines in the lungs compared to wild-type mice following A. fumigatus infection. The impaired clearance and cytokine production in ficolin knockout mice was independent of complement, as shown by equivalent levels of A. fumigatus-mediated complement activation in ficolin knockout mice and wild-type mice. In conclusion, this study demonstrates that ficolins are important in initial innate host defense against A. fumigatus infections in vivo.
烟曲霉是一种机会性真菌病原体，可在免疫功能低下的患者中引起严重的侵袭性感染。固有免疫在抵御烟曲霉感染中起主要作用。纤维胶凝蛋白是一类可溶性模式识别受体，能够激活补体的凝集素途径。此前的体外研究报道纤维胶凝蛋白可与烟曲霉结合，但其在体内宿主抗真菌感染中的作用尚不清楚。在本研究中，我们使用纤维胶凝蛋白缺陷小鼠来研究纤维胶凝蛋白在烟曲霉肺部感染过程中的作用。与野生型小鼠相比，纤维胶凝蛋白基因敲除小鼠在感染后24小时肺部的真菌载量显著更高。纤维胶凝蛋白基因敲除小鼠中烟曲霉清除延迟并非归因于炎症细胞募集受损。然而，研究发现，与野生型小鼠相比，烟曲霉感染后纤维胶凝蛋白基因敲除小鼠肺部促炎细胞因子的产生减少。纤维胶凝蛋白基因敲除小鼠清除功能受损和细胞因子产生减少与补体无关，因为在纤维胶凝蛋白基因敲除小鼠和野生型小鼠中烟曲霉介导的补体激活水平相当。总之，本研究表明纤维胶凝蛋白在体内宿主对烟曲霉感染的初始固有防御中起重要作用。
