Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles Medical Center, Torrance, CA 90502, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14194-9. doi: 10.1073/pnas.1117676109. Epub 2012 Aug 13.
The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans, in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3- and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts.
白色念珠菌是口咽念珠菌病（OPC）的主要病因。这种疾病的一个关键特征是真菌侵袭口腔上皮细胞，这个过程可以通过主动穿透和真菌诱导的内吞作用发生。两种侵袭素 Als3 和 Ssa1 诱导上皮细胞内吞白色念珠菌，部分是通过与 E-钙粘蛋白结合。然而，E-钙粘蛋白功能的抑制仅部分减少白色念珠菌的内吞作用，表明该生物体还有其他上皮细胞受体。在这里，我们表明 EGF 受体（EGFR）和 HER2 共同作用诱导白色念珠菌菌丝的内吞作用。EGFR 和 HER2 以 Als3 和 Ssa1 依赖的方式与白色念珠菌相互作用，并诱导受体自身磷酸化。体外上皮细胞内吞白色念珠菌的最大作用需要 EGFR 和 HER2 的信号传导。重要的是，口腔白色念珠菌感染刺激口腔黏膜中 EGFR 和 HER2 的磷酸化，而双重 EGFR 和 HER2 激酶抑制剂的治疗显著降低了这种磷酸化并减轻了 OPC 的严重程度。这些结果表明 EGFR 和 HER2 信号在 OPC 发病机制中的重要性，并表明通过靶向真菌相互作用的宿主细胞受体来治疗念珠菌感染的可行性。
