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PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.
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; Varner, Judith A.
Affiliation
  • Shepard RM; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Ghebremedhin A; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pratumchai I; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
  • Robinson SR; Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
  • Betts C; New England Regional Biosafety Laboratory, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
  • Hu J; Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA.
  • Sasik R; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Fisch KM; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zak J; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Chen H; Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Paradise M; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
  • Rivera J; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Amjad M; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Uchiyama S; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Seo H; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Campos AD; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Dayao DA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Tzipori S; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Piedra-Mora C; Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
  • Das S; Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
  • Hasteh F; Department of Comparative Pathobiology, Section of Pathology, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
  • Russo H; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Sun X; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Xu L; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • E Alexander LC; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Duran JM; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Odish M; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pretorius V; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kirchberger NC; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Chin SM; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • Von Schalscha T; Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA.
  • Cheresh D; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Morrey JD; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Alargova R; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
  • O'Connell B; Institute for Antiviral Research, Animal, Dairy, and Veterinary Science, Utah State University, Logan, UT 84322, USA.
  • Martinot TA; Infinity Pharmaceuticals, Cambridge, MA 02138, USA.
  • Patel SP; Infinity Pharmaceuticals, Cambridge, MA 02138, USA.
  • Nizet V; Infinity Pharmaceuticals, Cambridge, MA 02138, USA.
  • Martinot AJ; Department of Medicine/Medical Oncology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Coussens LM; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • Teijaro JR; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Varner JA; Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
Sci Transl Med ; 16(754): eadi6887, 2024 Jul 03.
Article in En | MEDLINE | ID: mdl-38959328
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Class Ib Phosphatidylinositol 3-Kinase / SARS-CoV-2 / COVID-19 / Inflammation Limits: Animals / Humans Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Class Ib Phosphatidylinositol 3-Kinase / SARS-CoV-2 / COVID-19 / Inflammation Limits: Animals / Humans Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Estados Unidos