Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to Candida species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens Candida albicans, Candida glabrata, and Candida auris. Neutrophil responses to Candida species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to Candida species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics.

中文翻译：

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脾酪氨酸激酶是中性粒细胞对念珠菌反应的关键调节剂。


侵袭性真菌感染构成致命威胁，患者死亡率高达 90%。侵袭性真菌感染的发病率正在增加，特别是在实体器官或骨髓移植后接受免疫调节剂、化疗或免疫抑制药物的患者中。此外，最近还开发了脾酪氨酸激酶（Syk）抑制剂，用于治疗难治性自身免疫和血液学适应症患者。中性粒细胞是对多种病原体（包括侵入性真菌）的最初先天细胞反应者。控制中性粒细胞识别真菌的一个核心过程是通过凝集素结合受体，其中许多受体依赖 Syk 进行细胞激活。我们之前证明 Syk 激活对于细胞激活、吞噬体成熟和巨噬细胞中吞噬的真菌病原体的消除至关重要。在这里，我们结合使用遗传和化学抑制剂方法来评估 Syk 在中性粒细胞对念珠菌物种反应中的重要性。我们利用表达 Cas9 的中性粒细胞祖细胞系来生成同基因野生型和 Syk 缺陷型中性粒细胞。 Syk 缺陷的中性粒细胞无法控制人类病原体白色念珠菌、光滑念珠菌和耳念珠菌。中性粒细胞对念珠菌的反应，包括活性氧和细胞因子（例如肿瘤坏死因子 α (TNF-α)）的产生、中性粒细胞胞外陷阱 (NET) 的形成、吞噬作用和中性粒细胞聚集，似乎严重依赖于赛克。 这些结果表明 Syk 在中性粒细胞对念珠菌物种的反应中发挥重要作用，并引起人们对随着 Syk 调节疗法的发展而增加的真菌感染的担忧。