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 that promote T cell exhaustion,
fibrosis, vascular leak, epithelial cell depletion, and fatal organ
damage. Neutrophils and macrophages recruited to pathogen infected lungs,
including SARS-CoV-2 infected lungs, express phosphatidylinositol 3-kinase
gamma (PI3Kg), a signaling protein that coordinately controls granulocyte
and monocyte trafficking to diseased tissues and immune suppressive,
pro-fibrotic transcription in myeloid cells. PI3Kg deletion and inhibition
with the clinical PI3Kg 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 PI3Kg in inflammatory lung disease
and support the potential use of PI3Kg inhibitors to suppress inflammation
in severe infectious diseases.