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. Overall design: 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.