PI3Kg inhibition circumvents inflammation and mortality in SARS-CoV-2 and other infections

Virulent infectious agents such as SARS-CoV-2 and Methicillin Resistant Staphylococcus Aureus (MRSA) induce tissue damage that recruits neutrophils and monocyte/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 (PI3K a signaling protein that coordinately controls granulocyte and monocyte trafficking to diseased tissues and immune suppressive, pro-fibrotic transcription in myeloid cells. PI3K deletion and inhibition with the clinical PI3K 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 PI3K in inflammatory lung disease and support the potential use of PI3K inhibitors to suppress inflammation in severe infectious diseases. Human ACE2 transgenic mice were inoculated with SARS-CoV-2 and treated with the PI3Kgamma inhbitor IPI-549 or vehicle. Lungs of treated mice (4 IPI-549 and 3 Vehicle) were isolated three days later and stored in TRIZOL until RNA was isolated, and ribodepleted libaries were synthesized and sequenced.