Pre-exposure to Candida glabrata protects Galleria mellonella against subsequent lethal fungal infections

Commensal fungi are an important part of human microbial community, among which Candida albicans and Candida glabrata are two common opportunistic pathogens. Unlike the high pathogenicity of C. albicans, C. glabrata is reported to show low pathogenicity to the host. Here, by using a Galleria mellonella infection model, we were able to confirm the much lower virulence of C. glabrata than C. albicans. Interestingly, pre-exposure to live C. glabrata (LCG) protects the larvae against subsequent various lethal fungal infections, including C. albicans, Candida tropicalis, and Cryptococcus neoformans. Inconsistently, heat-inactivated C. glabrata (HICG) pre-exposure can only protect against C. albicans or C. tropicalis re-infection, but not C. neoformans. Mechanistically, LCG or HICG pre-exposure enhanced the fungicidal activity of hemocytes against C. albicans or C. tropicalis. Meanwhile, LCG pre-exposure enhanced the humoral immunity by modulating the expression of fungal defending proteins in the cell-free hemolymph, which may contribute to the protection against C. neoformans. Together, this study suggests the important role of C. glabrata in enhancing host immunity, and demonstrates the great potential of G. mellonella model in studying the innate immune responses against infections.共生真菌是人体微生物群落的重要组成部分，其中白色念珠菌（Candida albicans）与光滑念珠菌（Candida glabrata）为两类常见的机会致病菌。相较于白色念珠菌的高致病性，已有研究证实光滑念珠菌对宿主的致病性较弱。本研究采用大蜡螟（Galleria mellonella）感染模型，证实了光滑念珠菌的毒力远低于白色念珠菌。值得注意的是，预先暴露于活的光滑念珠菌（live C. glabrata，LCG）可使幼虫免受后续多种致死性真菌感染，包括白色念珠菌、热带念珠菌（Candida tropicalis）及新生隐球菌（Cryptococcus neoformans）。与之相悖的是，预先暴露于热灭活光滑念珠菌（heat-inactivated C. glabrata，HICG）仅能抵御白色念珠菌或热带念珠菌的再次感染，无法对新生隐球菌感染提供保护。机制分析显示，预先暴露于活的或热灭活的光滑念珠菌，均可增强血细胞对白色念珠菌或热带念珠菌的杀伤活性。同时，预先暴露于活的光滑念珠菌可通过调控无细胞血淋巴中真菌防御蛋白的表达，增强宿主的体液免疫，这或许是其抵御新生隐球菌感染的核心保护机制。综上，本研究揭示了光滑念珠菌在增强宿主免疫中的关键作用，并证实了大蜡螟模型在抗感染固有免疫应答研究中的巨大应用潜力。