Preventing Candida albicans from subverting host plasminogen for invasive infection treatment

Candida albicans is a common fungal pathogen in humans that colonizes the skin and mucosal surfaces of the majority healthy individuals. How C. albicans disseminates into the bloodstream and causes life-threatening systemic infections in immunocompromised patients remains unclear. Plasminogen system activation can degrade a variety of structural proteins in vivo and is involved in several homeostatic processes. Here, for the first time, we characterized that C. albicans could capture and “subvert” host plasminogen to invade host epithelial cell surface barriers through cell-wall localized Eno1 protein. We found that the “subverted” plasminogen system plays an important role in development of invasive infection caused by C. albicans in mice. Base on this finding, we discovered a mouse monoclonal antibody (mAb) 12D9 targeting C. albicans Eno1, with high affinity to the 254FYKDGKYDL262 motif in α-helices 6, β-sheet 6 (H6S6) loop and direct blocking activity for C. albicans capture host plasminogen. mAb 12D9 could prevent C. albicans from invading human epithelial and endothelial cells, and displayed antifungal activity and synergistic effect with anidulafungin or fluconazole in proof-of-concept in vivo studies, suggesting that blocking the function of cell surface Eno1 was effective for controlling invasive infection caused by Candida spp. In summary, our study provides the evidence of C. albicans invading host by “subverting” plasminogen system, suggesting a potential novel treatment strategy for invasive fungal infections.

白色念珠菌（Candida albicans）是人类常见的真菌病原体，可定植于绝大多数健康个体的皮肤与黏膜表面。然而，白色念珠菌如何播散至血液，并在免疫功能低下患者体内引发危及生命的全身性感染，其具体机制至今尚未明确。纤溶酶原系统（plasminogen system）激活后可在体内降解多种结构蛋白，并参与多项稳态调控过程。本研究首次阐明，白色念珠菌可通过细胞壁定位的烯醇化酶1（Eno1）蛋白捕获并‘劫持’宿主纤溶酶原，从而突破宿主上皮细胞表面屏障。研究证实，被‘劫持’的纤溶酶原系统在小鼠白色念珠菌侵袭性感染的发生发展中发挥重要作用。基于上述发现，本研究开发了一株靶向白色念珠菌Eno1的小鼠源单克隆抗体（monoclonal antibody, mAb）12D9：该抗体对α螺旋6、β折叠6（H6S6）环区中254FYKDGKYDL262基序具有高亲和力，且可直接阻断白色念珠菌捕获宿主纤溶酶原的过程。单克隆抗体12D9可阻断白色念珠菌侵袭人类上皮细胞与内皮细胞；在概念验证体内实验中，该抗体展现出抗真菌活性，且与阿尼芬净（anidulafungin）、氟康唑（fluconazole）联用可产生协同效应，这提示阻断细胞表面Eno1的功能可有效管控念珠菌属（Candida spp.）引发的侵袭性感染。综上，本研究证实白色念珠菌可通过‘劫持’纤溶酶原系统侵袭宿主，为侵袭性真菌感染的新型治疗策略提供了实验依据。