Candida glabrata Binding to Candida albicans Hyphae Enables Its Development in Oropharyngeal Candidiasis

Pathogenic mechanisms of Candida glabrata in oral candidiasis, especially because of its inability to form hyphae, are understudied. Since both Candida albicans and C. glabrata are frequently co-isolated in oropharyngeal candidiasis (OPC), we examined their co-adhesion in vitro and observed adhesion of C. glabrata only to C. albicans hyphae microscopically. Mice were infected sublingually with C. albicans or C. glabrata individually, or with both species concurrently, to study their ability to cause OPC. Infection with C. glabrata alone resulted in negligible infection of tongues; however, colonization by C. glabrata was increased by co-infection or a pre-established infection with C. albicans. Furthermore, C. glabrata required C. albicans for colonization of tongues, since decreasing C. albicans burden with fluconazole also reduced C. glabrata. C. albicans hyphal wall adhesins Als1 and Als3 were important for in vitro adhesion of C. glabrata and to establish OPC. C. glabrata cell wall protein coding genes EPA8, EPA19, AWP2, AWP7, and CAGL0F00181 were implicated in mediating adhesion to C. albicans hyphae and remarkably, their expression was induced by incubation with germinated C. albicans. Thus, we found a near essential requirement for the presence of C. albicans for both initial colonization and establishment of OPC infection by C. glabrata.

光滑念珠菌（Candida glabrata）在口腔念珠菌病中的致病机制，尤其是因其无法形成菌丝，长期以来未得到充分研究。由于白色念珠菌（Candida albicans）与光滑念珠菌常可从口咽念珠菌病（oropharyngeal candidiasis, OPC）样本中共分离得到，我们开展了二者体外共黏附实验，并通过显微镜观察到光滑念珠菌仅能黏附于白色念珠菌菌丝。为探究二者引发口咽念珠菌病的能力，我们通过舌下接种的方式感染小鼠：分别单独接种白色念珠菌或光滑念珠菌，或同时接种两种菌株。仅接种光滑念珠菌的小鼠，其舌部感染程度可忽略不计；但当与白色念珠菌共感染，或预先感染白色念珠菌后再接种光滑念珠菌时，光滑念珠菌的舌部定植量会显著升高。此外，光滑念珠菌在舌部的定植完全依赖于白色念珠菌：使用氟康唑（fluconazole）降低白色念珠菌负荷后，光滑念珠菌的定植量也随之下降。白色念珠菌菌丝壁黏附素Als1与Als3，在光滑念珠菌体外黏附及口咽念珠菌病的建立过程中发挥了关键作用。光滑念珠菌细胞壁蛋白编码基因EPA8、EPA19、AWP2、AWP7及CAGL0F00181，被证实参与介导其与白色念珠菌菌丝的黏附过程；值得注意的是，这些基因的表达会在与萌发的白色念珠菌共培养时被显著诱导。综上，我们发现光滑念珠菌的初始定植与口咽念珠菌病的建立，几乎完全依赖于白色念珠菌的存在。