The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.侵袭性念珠菌病（Invasive candidiasis）主要由白色念珠菌（Candida albicans）引发，是一类致死率极高的严重医疗健康问题，尤其在免疫功能低下患者群体中危害更为显著。固有免疫细胞可表达病原识别受体（pathogen recognition receptors, PRRs），其中包括能够结合白色念珠菌以启动免疫应答的C型凝集素样受体（C-type lectin-like receptors, CLRs）。此前已有研究分别提出Dectin-1、Dectin-2与Mincle等多种C型凝集素样受体可参与针对白色念珠菌的免疫应答过程，但这些受体如何协同清除真菌感染的机制仍未明确。本研究借助新型多C型凝集素样受体基因敲除（knockout, KO）小鼠，解析了Dectin-1、Dectin-2与Mincle在全身性白色念珠菌感染过程中各自的作用、协同效应及整体功能。研究结果揭示了C型凝集素样受体协同作用在抗真菌免疫中此前未被重视的关键作用：多种C型凝集素样受体的联合保护效应显著强于单一受体，且该效应通过炎性单核细胞介导，具体机制包括识别并吞噬白色念珠菌，以及分泌白色念珠菌诱导产生的细胞因子与趋化因子。对于中性粒细胞介导的同类应答，此类C型凝集素样受体并非必需，这可能是因为相较于炎性单核细胞，中性粒细胞表面此类受体的表达水平更低。相较于单一C型凝集素样受体敲除小鼠，同时敲除Dectin-1与Dectin-2，或是敲除全部三种C型凝集素样受体的小鼠，对全身性白色念珠菌感染的易感性显著升高。多C型凝集素样受体敲除小鼠无法控制真菌增殖，原因在于其早期炎性单核细胞介导的免疫应答不足。面对过度增殖的真菌，这类小鼠会触发过度炎症反应，进而可能引发多器官功能衰竭。综上，本研究数据揭示了C型凝集素样受体协同作用在有效控制白色念珠菌感染、维持感染过程中器官功能方面的关键作用。