<i>MSS2</i> maintains mitochondrial function and is required for chitosan resistance, invasive growth, biofilm formation and virulence in <i>Candida albicans</i>
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<i>Candida albicans</i> is the most prevalent fungal pathogen in humans, particularly in immunocompromised patients. In this study, by screening a <i>C. albicans</i> mutant library, we first identified that the <i>MSS2</i> gene, an ortholog of <i>Saccharomyces cerevisiae MSS2</i> required for mitochondrial respiration, mediates chitosan resistance. Upon treatment with 0.2% chitosan, the growth of <i>mss2Δ</i> strains was strikingly impaired, and <i>MSS2</i> expression was significantly repressed by chitosan. Furthermore, <i>mss2Δ</i> strains exhibited slow growth on medium supplemented with glycerol as the sole carbon source. Similar to the chitosan-treated wild-type strain, the <i>mss2Δ</i> strain exhibited a significantly impaired ATP production ability. These data suggest that an antifungal mechanism of chitosan against <i>C. albicans</i> acts by inhibiting <i>MSS2</i> gene expression, leading to repression of mitochondrial function. Normal respiratory function is suggested to be required for fungal virulence. Interestingly, the <i>mss2Δ</i> mutant strains exhibited significantly impaired invasive ability <i>in vitro</i> and <i>ex vivo</i> but retained normal hyphal development ability in liquid medium. Furthermore, the <i>MSS2</i> deletion strains could not form robust biofilms and exhibited significantly reduced virulence. Collectively, these results demonstrated that the antifungal effect of chitosan against <i>C. albicans</i> is mediated via inhibition of mitochondrial biogenesis. These data may provide another strategy for antifungal drug development via inhibition of fungal mitochondria.
白色念珠菌（Candida albicans）是人类最常见的致病性真菌，尤其多见于免疫功能低下患者。本研究通过筛选白色念珠菌突变体文库，首次鉴定出线粒体呼吸所必需的酿酒酵母（Saccharomyces cerevisiae）MSS2基因的同源基因MSS2可介导对壳聚糖的抗性。经0.2%壳聚糖处理后，mss2Δ菌株的生长受到显著抑制，且壳聚糖可显著抑制MSS2基因的表达。进一步研究发现，mss2Δ菌株在以甘油为唯一碳源的培养基上生长缓慢。与经壳聚糖处理的野生型菌株类似，mss2Δ菌株的ATP生成能力显著受损。上述数据表明，壳聚糖抗白色念珠菌的抑菌机制之一是通过抑制MSS2基因表达，进而抑制线粒体功能。现有研究提示，真菌毒力的维持需要正常的呼吸功能。有趣的是，mss2Δ突变株在体外及离体实验中的侵袭能力显著受损，但在液体培养基中仍可维持正常的菌丝发育能力。此外，MSS2基因缺失菌株无法形成稳定的生物被膜，且毒力显著降低。综上，本研究证实壳聚糖对白色念珠菌的抑菌作用是通过抑制线粒体生物发生介导的。本研究结果或可为通过抑制真菌线粒体开发抗真菌药物提供新的策略。
