PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections-Reference-Cited by-同舟云学术

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections

Published:2024-07-03 Issue:754 Volume:16 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Shepard Ryan M.¹^ORCID,Ghebremedhin Anghesom¹^ORCID,Pratumchai Isaraphorn²^ORCID,Robinson Sally R.³⁴^ORCID,Betts Courtney⁵,Hu Jingjing⁶,Sasik Roman⁷^ORCID,Fisch Kathleen M.⁷⁸^ORCID,Zak Jaroslav²^ORCID,Chen Hui¹,Paradise Marc¹,Rivera Jason¹,Amjad Mohammad¹,Uchiyama Satoshi⁹,Seo Hideya⁹^ORCID,Campos Alejandro D.⁶^ORCID,Dayao Denise Ann³^ORCID,Tzipori Saul³,Piedra-Mora Cesar¹⁰^ORCID,Das Soumita⁶^ORCID,Hasteh Farnaz⁶,Russo Hana⁶^ORCID,Sun Xin⁹^ORCID,Xu Le⁹^ORCID,E. Alexander Laura Crotty¹¹^ORCID,Duran Jason M.¹¹^ORCID,Odish Mazen¹¹^ORCID,Pretorius Victor¹²^ORCID,Kirchberger Nell C.⁵^ORCID,Chin Shao-ming¹^ORCID,Von Schalscha Tami⁶^ORCID,Cheresh David⁶^ORCID,Morrey John D.¹³,Alargova Rossitza¹⁴,O’Connell Brenda¹⁴,Martinot Theodore A.¹⁴^ORCID,Patel Sandip P.¹⁵,Nizet Victor⁹¹⁶^ORCID,Martinot Amanda J.³⁴¹⁰^ORCID,Coussens Lisa M.⁵¹⁷^ORCID,Teijaro John R.²^ORCID,Varner Judith A.¹⁶^ORCID

Affiliation:

1. Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

2. Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.

3. Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.

4. New England Regional Biosafety Laboratory, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.

5. Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA.

6. Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.

7. Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.

8. Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

9. Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.

10. Department of Comparative Pathobiology, Section of Pathology, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.

11. Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

12. Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.

13. Institute for Antiviral Research, Animal, Dairy, and Veterinary Science, Utah State University, Logan, UT 84322, USA.

14. Infinity Pharmaceuticals, Cambridge, MA 02138, USA.

15. Department of Medicine/Medical Oncology, University of California, San Diego, La Jolla, CA 92093, USA.

16. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

17. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.adi6887

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