Targeting mTOR in myeloid cells prevents infection-associated inflammation

Authors

• Yohana C. Toner, Icahn School of Medicine at Mount Sinai
• Jazz Munitz, Icahn School of Medicine at Mount Sinai
• Geoffrey Prevot, Icahn School of Medicine at Mount Sinai
• Judit Morla-Folch, Icahn School of Medicine at Mount Sinai
• William Wang, Icahn School of Medicine at Mount Sinai
• Yuri van Elsas, Icahn School of Medicine at Mount Sinai
• Bram Priem, Icahn School of Medicine at Mount Sinai
• Jeroen Deckers, Icahn School of Medicine at Mount Sinai
• Tom Anbergen, Icahn School of Medicine at Mount Sinai
• Thijs J. Beldman, Radboud University Nijmegen
• Eliane E.S. Brechbühl, Icahn School of Medicine at Mount Sinai
• Muhammed D. Aksu, Radboud University Nijmegen
• Athanasios Ziogas, Radboud University Nijmegen
• Sebastian A. Sarlea, Radboud University Nijmegen
• Mumin Ozturk, Radboud University Nijmegen
• Zhenhua Zhang, Helmholtz Centre for Infection Research (HZI)
• Wenchao Li, Helmholtz Centre for Infection Research (HZI)
• Yang Li, Radboud University Nijmegen
• Alexander Maier, Icahn School of Medicine at Mount Sinai
• Jessica C. Fernandes, Icahn School of Medicine at Mount Sinai
• Glenn A.O. Cremers, Trained Therapeutix Discovery
• Bas van Genabeek, Trained Therapeutix Discovery
• Joost H.C.M. Kreijtz, Trained Therapeutix Discovery
• Esther Lutgens, Mayo Clinic Rochester
• Niels P. Riksen, Radboud University Nijmegen
• Henk M. Janssen, SyMO-Chem B.V.
• Serge H.M. Söntjens, SyMO-Chem B.V.
• Freek J.M. Hoeben, SyMO-Chem B.V.

Abstract

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using ¹⁸F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

Document Type

Article

Publication Date

4-18-2025

Notes/Citation Information

Publisher Copyright: © 2025 The Author(s)

Digital Object Identifier (DOI)

10.1016/j.isci.2025.112163

Archival?

Archival

Repository Citation

Toner, Yohana C.; Munitz, Jazz; Prevot, Geoffrey; Morla-Folch, Judit; Wang, William; van Elsas, Yuri; Priem, Bram; Deckers, Jeroen; Anbergen, Tom; Beldman, Thijs J.; Brechbühl, Eliane E.S.; Aksu, Muhammed D.; Ziogas, Athanasios; Sarlea, Sebastian A.; Ozturk, Mumin; Zhang, Zhenhua; Li, Wenchao; Li, Yang; Maier, Alexander; Fernandes, Jessica C.; Cremers, Glenn A.O.; van Genabeek, Bas; Kreijtz, Joost H.C.M.; Lutgens, Esther; Riksen, Niels P.; Janssen, Henk M.; Söntjens, Serge H.M.; and Hoeben, Freek J.M., "Targeting mTOR in myeloid cells prevents infection-associated inflammation" (2025). Physiology Faculty Publications. 255.
https://uknowledge.uky.edu/physiology_facpub/255