Abstract：
Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.
摘要：
严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）和耐甲氧西林金黄色葡萄球菌（MRSA）等强传染性病原体引起组织损伤，招募中性粒细胞，单核细胞,和巨噬细胞，导致T细胞耗尽,纤维化，血管渗漏,上皮细胞耗竭，和致命的器官损伤。中性粒细胞,单核细胞,和巨噬细胞招募到病原体感染的肺部，包括SARS-CoV-2感染的肺部,表达磷脂酰肌醇3-激酶γ（PI3Kγ），一种信号蛋白，协调粒细胞和单核细胞向患病组织的运输和免疫抑制，骨髓细胞中的促纤维化转录。PI3Kγ缺失和用临床PI3Kγ抑制剂eganelisib抑制可促进感染性疾病模型的存活，包括SARS-CoV-2和MRSA,通过抑制炎症，血管渗漏,器官损伤,和细胞因子风暴。这些结果证明了PI3Kγ在炎症性肺病中的重要作用，并支持PI3Kγ抑制剂在严重感染性疾病中抑制炎症的潜在用途。
