The protective effect of inflammatory monocytes during systemic <i>C</i>. <i>albicans</i> 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）主要由白念珠菌（Candida albicans）引起，是一类致死率居高的严重医疗相关问题，尤其好发于免疫功能低下患者群体。先天免疫细胞（innate immune cells）可表达包括C型凝集素样受体（C-type lectin-like receptors，CLRs）在内的病原体识别受体（pathogen recognition receptors，PRRs），此类受体能够结合白念珠菌，进而启动免疫应答反应。既往研究已分别提出Dectin-1、Dectin-2与Mincle等多种CLRs参与抗白念珠菌的免疫应答，但目前尚不明确这些受体如何协同清除真菌感染。本研究借助新型多CLRs敲除（knockout，KO）小鼠模型，解析了Dectin-1、Dectin-2及Mincle在系统性白念珠菌感染过程中的单独作用、协同效应与整体功能。研究结果揭示了CLR协同在抗真菌免疫中此前未被充分认知的重要作用。多种CLRs联合的保护效果显著优于单一受体，其保护作用通过炎性单核细胞（inflammatory monocytes）介导，具体机制包括识别并吞噬白念珠菌、分泌白念珠菌诱导产生的细胞因子（cytokines）与趋化因子（chemokines）。此类CLRs对于介导中性粒细胞（neutrophils）的同类应答并非必需，这一现象可能源于相较于炎性单核细胞，中性粒细胞表面这些CLRs的表达水平更低。与单一CLR敲除小鼠相比，同时敲除Dectin-1与Dectin-2，或同时敲除三种CLRs的小鼠，对系统性白念珠菌感染的易感性大幅升高。多CLRs敲除小鼠无法有效控制真菌增殖，其原因在于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，多CLRs敲除小鼠会触发过度炎症应答，这可能最终导致多器官功能衰竭。综上，本研究数据明确了CLR协同在有效控制白念珠菌感染以及维持感染期间器官功能中的关键作用。