iScience (Apr 2025)
Targeting mTOR in myeloid cells prevents infection-associated inflammation
- Yohana C. Toner,
- Jazz Munitz,
- Geoffrey Prevot,
- Judit Morla-Folch,
- William Wang,
- Yuri van Elsas,
- Bram Priem,
- Jeroen Deckers,
- Tom Anbergen,
- Thijs J. Beldman,
- Eliane E.S. Brechbühl,
- Muhammed D. Aksu,
- Athanasios Ziogas,
- Sebastian A. Sarlea,
- Mumin Ozturk,
- Zhenhua Zhang,
- Wenchao Li,
- Yang Li,
- Alexander Maier,
- Jessica C. Fernandes,
- Glenn A.O. Cremers,
- Bas van Genabeek,
- Joost H.C.M. Kreijtz,
- Esther Lutgens,
- Niels P. Riksen,
- Henk M. Janssen,
- Serge H.M. Söntjens,
- Freek J.M. Hoeben,
- Ewelina Kluza,
- Gagandeep Singh,
- Evangelos J. Giamarellos-Bourboulis,
- Michael Schotsaert,
- Raphaël Duivenvoorden,
- Roy van der Meel,
- Leo A.B. Joosten,
- Lei Cai,
- Ryan E. Temel,
- Zahi A. Fayad,
- Musa M. Mhlanga,
- Mandy M.T. van Leent,
- Abraham J.P. Teunissen,
- Mihai G. Netea,
- Willem J.M. Mulder
Affiliations
- Yohana C. Toner
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Jazz Munitz
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Geoffrey Prevot
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Judit Morla-Folch
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- William Wang
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Yuri van Elsas
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Bram Priem
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Jeroen Deckers
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Tom Anbergen
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Thijs J. Beldman
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Eliane E.S. Brechbühl
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
- Muhammed D. Aksu
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Athanasios Ziogas
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Sebastian A. Sarlea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Mumin Ozturk
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Epigenomics & Single Cell Biophysics Group, Department of Cell Biology, FNWI, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525 GA Nijmegen, the Netherlands
- Zhenhua Zhang
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
- Wenchao Li
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
- Yang Li
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
- Alexander Maier
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cardiology and Angiology, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Jessica C. Fernandes
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Glenn A.O. Cremers
- Trained Therapeutix Discovery, 5349 AB Oss, the Netherlands
- Bas van Genabeek
- Trained Therapeutix Discovery, 5349 AB Oss, the Netherlands; SyMO-Chem B.V., 5612 AZ Eindhoven, the Netherlands
- Joost H.C.M. Kreijtz
- Trained Therapeutix Discovery, 5349 AB Oss, the Netherlands
- Esther Lutgens
- Department of Cardiovascular Medicine, Experimental Cardiovascular Immunology Laboratory, Mayo Clinic, Rochester, MN 55905, USA
- Niels P. Riksen
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Henk M. Janssen
- SyMO-Chem B.V., 5612 AZ Eindhoven, the Netherlands
- Serge H.M. Söntjens
- SyMO-Chem B.V., 5612 AZ Eindhoven, the Netherlands
- Freek J.M. Hoeben
- SyMO-Chem B.V., 5612 AZ Eindhoven, the Netherlands
- Ewelina Kluza
- Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands
- Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Evangelos J. Giamarellos-Bourboulis
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, 124 62 Athens, Greece
- Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Raphaël Duivenvoorden
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Nephrology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Roy van der Meel
- Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands
- Leo A.B. Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400 349 Cluj-Napoca, Romania
- Lei Cai
- Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA
- Ryan E. Temel
- Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA
- Zahi A. Fayad
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Musa M. Mhlanga
- Epigenomics & Single Cell Biophysics Group, Department of Cell Biology, FNWI, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525 GA Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
- Mandy M.T. van Leent
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Abraham J.P. Teunissen
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany
- Willem J.M. Mulder
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands; Corresponding author
- Journal volume & issue
-
Vol. 28,
no. 4
p. 112163
Abstract
Summary: 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.
