PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections,Science Translational Medicine

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PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections
Science Translational Medicine ( IF 15.8 ) Pub Date : 2024-07-03 , DOI: 10.1126/scitranslmed.adi6887
Ryan M Shepard ₁ , Anghesom Ghebremedhin ₁ , Isaraphorn Pratumchai ₂ , Sally R Robinson _{3,

4} , Courtney Betts ₅ , Jingjing Hu ₆ , Roman Sasik ₇ , Kathleen M Fisch _{7,

8} , Jaroslav Zak ₂ , Hui Chen ₁ , Marc Paradise ₁ , Jason Rivera ₁ , Mohammad Amjad ₁ , Satoshi Uchiyama ₉ , Hideya Seo ₉ , Alejandro D Campos ₆ , Denise Ann Dayao ₃ , Saul Tzipori ₃ , Cesar Piedra-Mora ₁₀ , Soumita Das ₆ , Farnaz Hasteh ₆ , Hana Russo ₆ , Xin Sun ₉ , Le Xu ₉ , Laura Crotty E Alexander ₁₁ , Jason M Duran ₁₁ , Mazen Odish ₁₁ , Victor Pretorius ₁₂ , Nell C Kirchberger ₅ , Shao-Ming Chin ₁ , Tami Von Schalscha ₆ , David Cheresh ₆ , John D Morrey ₁₃ , Rossitza Alargova ₁₄ , Brenda O'Connell ₁₄ , Theodore A Martinot ₁₄ , Sandip P Patel ₁₅ , Victor Nizet _{9,

16} , Amanda J Martinot _{3,

4,

10} , Lisa M Coussens _{5,

17} , John R Teijaro ₂ , Judith A Varner _{1,

6}

Affiliation

Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
New England Regional Biosafety Laboratory, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA.
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Comparative Pathobiology, Section of Pathology, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
Institute for Antiviral Research, Animal, Dairy, and Veterinary Science, Utah State University, Logan, UT 84322, USA.
Infinity Pharmaceuticals, Cambridge, MA 02138, USA.
Department of Medicine/Medical Oncology, University of California, San Diego, La Jolla, CA 92093, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.

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.

中文翻译：

PI3Kγ 抑制可避免 SARS-CoV-2 和其他感染中的炎症和血管渗漏

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 和甲氧西林耐药等强毒传染原金黄色葡萄球菌(MRSA) 会引起组织损伤，募集中性粒细胞、单核细胞和巨噬细胞，导致 T 细胞耗竭、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被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)，这是一种信号蛋白，可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 缺失和临床 PI3Kγ 抑制剂 eganelisib 的抑制可通过抑制炎症、血管渗漏、器官损伤和细胞因子风暴，促进传染病模型（包括 SARS-CoV-2 和 MRSA）的存活。这些结果证明了 PI3Kγ 在炎症性肺部疾病中的重要作用，并支持 PI3Kγ 抑制剂在严重传染病中抑制炎症的潜在用途。

更新日期：2024-07-03

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