Pneumocystis jirovecii, the opportunistic fungus that causes Pneumocystis pneumonia (PCP) in humans, is a significant contributor to morbidity and mortality in immunocompromised patients. Given the profound deleterious inflammatory effects of the major β-glucan cell wall carbohydrate constituents of Pneumocystis through Dectin-1 engagement and downstream caspase recruitment domain-containing protein 9 (CARD9) immune activation, we sought to determine whether the pharmacodynamic activity of the known CARD9 inhibitor BRD5529 might have a therapeutic effect on macrophage innate immune signaling and subsequent downstream anti-inflammatory activity. The small-molecule inhibitor BRD5529 was able to significantly reduce both phospho-p38 and phospho-pERK1 signaling and tumor necrosis factor alpha (TNF-α) release during stimulation of macrophages with Pneumocystis cell wall β-glucans.

中文翻译：

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使用小分子疗法靶向 CARD9 可抑制对卡氏肺囊虫β-葡聚糖的先天免疫信号传导和炎症反应。

Pneumocystis jirovecii是导致人类肺孢子菌肺炎 (PCP)的机会性真菌，是导致免疫功能低下患者发病率和死亡率的重要因素。鉴于肺孢子菌的主要 β-葡聚糖细胞壁碳水化合物成分具有严重的有害炎症作用通过 Dectin-1 参与和下游含有半胱天冬酶募集结构域的蛋白 9 (CARD9) 免疫激活，我们试图确定已知 CARD9 抑制剂 BRD5529 的药效学活性是否可能对巨噬细胞先天免疫信号和随后的下游抗炎具有治疗作用活动。小分子抑制剂BRD5529能够显著减少与巨噬细胞的刺激过程中既磷酸化p38和磷酸化磷酸化ERK1信令和肿瘤坏死因子α（TNF-α）释放肺细胞壁β葡聚糖。