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An IL-17F.S65L Knock-In Mouse Reveals Similarities and Differences in IL-17F Function in Oral Candidiasis: A New Tool to Understand IL-17F
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-29 , DOI: 10.4049/jimmunol.2000394
Chunsheng Zhou 1 , Leticia Monin 1 , Rachael Gordon 2 , Felix E Y Aggor 1 , Rami Bechara 1 , Tara N Edwards 3 , Daniel H Kaplan 3 , Sebastien Gingras 2 , Sarah L Gaffen 4
Affiliation  

Key Points A murine IL-17F.S65L ortholog recapitulates the impaired signaling function in vitro. IL-17F.S65L knock-in mice are susceptible to oral candidiasis, unlike Il17f−/− mice. Il17fS65L/S65L mice may be a broadly valuable tool to interrogate IL-17F function. Visual Abstract Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans. IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this “experiment of nature” by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9. Unlike Il17f−/− mice that are resistant to OPC, Il17fS65L/S65L mice showed increased oral fungal burdens similar to Il17a−/− mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f−/− mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.

中文翻译:

IL-17F.S65L 敲入小鼠揭示口腔念珠菌病中 IL-17F 功能的异同:了解 IL-17F 的新工具

关键点 鼠 IL-17F.S65L 直向同源物在体外概括了受损的信号传导功能。与 Il17f-/- 小鼠不同,IL-17F.S65L 敲入小鼠易患口腔念珠菌病。Il17fS65L/S65L 小鼠可能是研究 IL-17F 功能的广泛有价值的工具。视觉摘要 口咽念珠菌病 (OPC) 是由共生真菌白色念珠菌引起的口腔黏膜机会性感染。IL-17R 信号传导对于预防小鼠和人类的 OPC 至关重要,但其配体 IL-17A、IL-17F 和 IL-17AF 的个别作用尚不清楚。小鼠中纯合子 IL-17F 缺乏不会导致 OPC 易感性,而缺乏 IL-17A 的小鼠则中等易感。在人类中,鉴定出 IL-17F (IL-17F.S65L) 中罕见的杂合突变,可导致慢性皮肤粘膜念珠菌病,表明存在由 IL-17F 和/或 IL-17AF 介导的重要抗真菌途径。为了更详细地研究 IL-17F 和 IL-17AF 的作用,我们通过创建一个带有 CRISPR/Cas9 IL-17F (Ser65Leu) 同源突变的小鼠品系,利用了这一“自然实验”。与对 OPC 具有抗性的 Il17f-/- 小鼠不同,Il17fS65L/S65L 小鼠的口腔真菌负担增加,类似于 Il17a-/- 小鼠。然而,与人类相反,疾病仅在纯合子而非杂合子突变小鼠中明显。该突变与适度受损的 CXC 趋化因子表达和中性粒细胞募集到受感染的舌头有关,但与口服抗菌肽表达的改变无关。这些发现表明了神秘的细胞因子 IL-17F 有助于宿主防御真菌的机制。而且,
更新日期:2020-06-29
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