No abstract

Invasive candidiasis (IC) is one of the leading causes of death among immunocompromised patients. Because of limited effective therapy treatment options, prevention of IC through vaccine is an appealing strategy. However, how to induce the generation of direct candidacidal antibodies in host remains unclear. Gpi7 mutant C. albicans is an avirulent strain that exposes cell wall β-(1,3)-glucans. Here, we found that vaccination with the gpi7 mutant strain could protect mice against invasive candidiasis caused by C. albicans and non- albicans Candida spp. The protective effects induced by gpi7 mutant relied on long-lived plasma cells (LLPCs) secreting protective antibodies against C. albicans . Clinically, we verified a similar profile of IgG antibodies in the serum samples from patients recovering from IC to those from gpi7 mutant-vaccinated mice. Mechanistically, we found cell wall β-(1,3)-glucan of gpi7 mutant facilitated Dectin-1 receptor dependent nuclear translocation of non-canonical NF-κB subunit RelB in macrophages and subsequent IL-18 secretion, which primed protective antibodies generation in vivo . Together, our study demonstrate that Dectin-1 engagement could trigger RelB activation to prime IL-18 expression and established a new paradigm for consideration of the link between Dectin-1 mediated innate immune response and adaptive humoral immunity, suggesting a previously unknown active vaccination strategy against Candida spp. infection.

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 254 FYKDGKYDL 262 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.