1. PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections
- Author
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Shepard, Ryan M, Ghebremedhin, Anghesom, Pratumchai, Isaraphorn, Robinson, Sally R, Betts, Courtney, Hu, Jingjing, Sasik, Roman, Fisch, Kathleen M, Zak, Jaroslav, Chen, Hui, Paradise, Marc, Rivera, Jason, Amjad, Mohammad, Uchiyama, Satoshi, Seo, Hideya, Campos, Alejandro D, Dayao, Denise Ann, Tzipori, Saul, Piedra-Mora, Cesar, Das, Soumita, Hasteh, Farnaz, Russo, Hana, Sun, Xin, Xu, Le, E Alexander, Laura Crotty, Duran, Jason M, Odish, Mazen, Pretorius, Victor, Kirchberger, Nell C, Chin, Shao-Ming, Von Schalscha, Tami, Cheresh, David, Morrey, John D, Alargova, Rossitza, O'Connell, Brenda, Martinot, Theodore A, Patel, Sandip P, Nizet, Victor, Martinot, Amanda J, Coussens, Lisa M, Teijaro, John R, and Varner, Judith A
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Coronaviruses ,Emerging Infectious Diseases ,Biodefense ,Infectious Diseases ,Lung ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,COVID-19 ,Class Ib Phosphatidylinositol 3-Kinase ,SARS-CoV-2 ,Animals ,Inflammation ,Humans ,COVID-19 Drug Treatment ,Methicillin-Resistant Staphylococcus aureus ,Mice ,Phosphoinositide-3 Kinase Inhibitors ,Cytokine Release Syndrome ,Capillary Permeability ,Mice ,Inbred C57BL ,Staphylococcal Infections ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - 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.
- Published
- 2024