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

Ryan M. Shepard; Anghesom Ghebremedhin; Isaraphorn Pratumchai; Sally R. Robinson; Courtney Betts; Jingjing Hu; Roman Sasik; Kathleen M. Fisch; Jaroslav Zak; Hui Chen; Marc Paradise; Jason Rivera; Mohammad Amjad; Satoshi Uchiyama; Hideya Seo; Alejandro D. Campos; Denise Ann Dayao; Saul Tzipori; Cesar Piedra-Mora; Soumita Das; Farnaz Hasteh; Hana Russo; Xin Sun; Le Xu; Laura Crotty E. Alexander; Jason M. Duran; Mazen Odish; Victor Pretorius; Nell C. Kirchberger; Shao Ming Chin; Tami Von Schalscha; David Cheresh; John D. Morrey; Rossitza Alargova; Brenda O’Connell; Theodore A. Martinot; Sandip P. Patel; Victor Nizet; Amanda J. Martinot; Lisa M. Coussens; John R. Teijaro; Judith A. Varner

doi:10.1126/scitranslmed.adi6887

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

Ryan M. Shepard, Anghesom Ghebremedhin, Isaraphorn Pratumchai, Sally R. Robinson, Courtney Betts, Jingjing Hu, Roman Sasik, Kathleen M. Fisch, Jaroslav Zak, Hui Chen, Marc Paradise, Jason Rivera, Mohammad Amjad, Satoshi Uchiyama, Hideya Seo, Alejandro D. Campos, Denise Ann Dayao, Saul Tzipori, Cesar Piedra-Mora, Soumita DasFarnaz Hasteh, Hana Russo, Xin Sun, Le Xu, Laura Crotty E. Alexander, Jason M. Duran, Mazen Odish, Victor Pretorius, Nell C. Kirchberger, Shao Ming Chin, Tami Von Schalscha, David Cheresh, John D. Morrey, Rossitza Alargova, Brenda O’Connell, Theodore A. Martinot, Sandip P. Patel, Victor Nizet, Amanda J. Martinot, Lisa M. Coussens, John R. Teijaro, Judith A. Varner

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	adi6887
Journal	Science translational medicine
Volume	16
Issue number	754
DOIs	https://doi.org/10.1126/scitranslmed.adi6887
State	Published - 2024

ASJC Scopus subject areas

General Medicine

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Shepard, R. M., Ghebremedhin, A., Pratumchai, I., Robinson, S. R., Betts, C., Hu, J., Sasik, R., Fisch, K. M., Zak, J., Chen, H., Paradise, M., Rivera, J., Amjad, M., Uchiyama, S., Seo, H., Campos, A. D., Dayao, D. A., Tzipori, S., Piedra-Mora, C., ... Varner, J. A. (2024). PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections. Science translational medicine, 16(754), Article adi6887. https://doi.org/10.1126/scitranslmed.adi6887

Shepard, RM, Ghebremedhin, A, Pratumchai, I, Robinson, SR, Betts, C, Hu, J, Sasik, R, Fisch, KM, Zak, J, Chen, H, Paradise, M, Rivera, J, Amjad, M, Uchiyama, S, Seo, H, Campos, AD, Dayao, DA, Tzipori, S, Piedra-Mora, C, Das, S, Hasteh, F, Russo, H, Sun, X, Xu, L, Alexander, LCE, Duran, JM, Odish, M, Pretorius, V, Kirchberger, NC, Chin, SM, Schalscha, TV, Cheresh, D, Morrey, JD, Alargova, R, O’Connell, B, Martinot, TA, Patel, SP, Nizet, V, Martinot, AJ, Coussens, LM, Teijaro, JR & Varner, JA 2024, 'PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections', Science translational medicine, vol. 16, no. 754, adi6887. https://doi.org/10.1126/scitranslmed.adi6887

@article{1adcb031d2c34d7499ea125613404c6a,

title = "PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections",

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.",

author = "Shepard, {Ryan M.} and Anghesom Ghebremedhin and Isaraphorn Pratumchai and Robinson, {Sally R.} and Courtney Betts and Jingjing Hu and Roman Sasik and Fisch, {Kathleen M.} and Jaroslav Zak and Hui Chen and Marc Paradise and Jason Rivera and Mohammad Amjad and Satoshi Uchiyama and Hideya Seo and Campos, {Alejandro D.} and Dayao, {Denise Ann} and Saul Tzipori and Cesar Piedra-Mora and Soumita Das and Farnaz Hasteh and Hana Russo and Xin Sun and Le Xu and Alexander, {Laura Crotty E.} and Duran, {Jason M.} and Mazen Odish and Victor Pretorius and Kirchberger, {Nell C.} and Chin, {Shao Ming} and Schalscha, {Tami Von} and David Cheresh and Morrey, {John D.} and Rossitza Alargova and Brenda O{\textquoteright}Connell and Martinot, {Theodore A.} and Patel, {Sandip P.} and Victor Nizet and Martinot, {Amanda J.} and Coussens, {Lisa M.} and Teijaro, {John R.} and Varner, {Judith A.}",

year = "2024",

doi = "10.1126/scitranslmed.adi6887",

language = "English (US)",

volume = "16",

journal = "Science translational medicine",

issn = "1946-6234",

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T1 - PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections

AU - Shepard, Ryan M.

AU - Ghebremedhin, Anghesom

AU - Pratumchai, Isaraphorn

AU - Robinson, Sally R.

AU - Betts, Courtney

AU - Hu, Jingjing

AU - Sasik, Roman

AU - Fisch, Kathleen M.

AU - Zak, Jaroslav

AU - Chen, Hui

AU - Paradise, Marc

AU - Rivera, Jason

AU - Amjad, Mohammad

AU - Uchiyama, Satoshi

AU - Seo, Hideya

AU - Campos, Alejandro D.

AU - Dayao, Denise Ann

AU - Tzipori, Saul

AU - Piedra-Mora, Cesar

AU - Das, Soumita

AU - Hasteh, Farnaz

AU - Russo, Hana

AU - Sun, Xin

AU - Xu, Le

AU - Alexander, Laura Crotty E.

AU - Duran, Jason M.

AU - Odish, Mazen

AU - Pretorius, Victor

AU - Kirchberger, Nell C.

AU - Chin, Shao Ming

AU - Schalscha, Tami Von

AU - Cheresh, David

AU - Morrey, John D.

AU - Alargova, Rossitza

AU - O’Connell, Brenda

AU - Martinot, Theodore A.

AU - Patel, Sandip P.

AU - Nizet, Victor

AU - Martinot, Amanda J.

AU - Coussens, Lisa M.

AU - Teijaro, John R.

AU - Varner, Judith A.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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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AN - SCOPUS:85197724666

SN - 1946-6234

VL - 16

JO - Science translational medicine

JF - Science translational medicine

IS - 754

M1 - adi6887

ER -

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

Abstract

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