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

doi:10.1016/j.isci.2025.112163

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

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

8 Scopus citations

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.

Original language	English
Article number	112163
Journal	iScience
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2025.112163
State	Published - Apr 18 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s)

Funding

We thank Heiner Schaal for providing us with the heat-inactivated SARS-CoV-2 Wuhan-Hu-1 variant and Professor David Williams for providing us with (β-1,3-(D)-glucan. This work was funded by W.J.M.M's NIHNHLBI (R01 HL144072 and P01 HL131478), NIHNIAID (P01 AI168258), NWO Vici (91818622), ERC Advanced Grant TOLERANCE (101019807), Leducq Foundation CHECKPOINT ATHERO and Trained Therapeutix Discovery. R.v.d.M. was supported by a Dutch Research Council (NWO) Vidi grant (19681). E.J.G.-B. was supported by the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). SARS-CoV-2 research in the M.S. lab is further supported by NIH NIAID R01 AI160706 and R01 DK130425. We thank Heiner Schaal for providing us with the heat-inactivated SARS-CoV-2 Wuhan-Hu-1 variant and Professor David Williams for providing us with (β-1,3-(D)-glucan. This work was funded by NIHNHLBI ( R01 HL144072 and P01 HL131478 ), NIHNIAID ( P01 AI168258 ), NWO Vici ( 91818622 ), ERC Advanced Grant TOLERANCE, Leducq Foundation CHECKPOINT ATHERO and Trained Therapeutix Discovery. E.J.G.-B. was supported by the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). SARS-CoV-2 research in the M.S. lab is further supported by NIH NIAID R01 AI160706 and R01 DK130425 .

Funders	Funder number
W.J.M.M's NIHNHLBI
Hellenic Institute for the Study of Sepsis
Fondation Leducq
Horizon 2020 European Grants ImmunoSep
Engineering Research Centers	101019807
NIHNIAID	P01 AI168258
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	19681, 91818622
NIHNHLBI	P01 HL131478, R01 HL144072
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...	R01 AI160706, R01 DK130425
Horizon Health Network	EPIC-CROWN-2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Biochemistry
Biological sciences
Immunology
Natural sciences

ASJC Scopus subject areas

General

Access to Document

10.1016/j.isci.2025.112163

Cite this

Toner, Y. C., Munitz, J., Prevot, G., Morla-Folch, J., Wang, W., van Elsas, Y., Priem, B., Deckers, J., Anbergen, T., Beldman, T. J., Brechbühl, E. E. S., Aksu, M. D., Ziogas, A., Sarlea, S. A., Ozturk, M., Zhang, Z., Li, W., Li, Y., Maier, A., ... Mulder, W. J. M. (2025). Targeting mTOR in myeloid cells prevents infection-associated inflammation. iScience, 28(4), Article 112163. https://doi.org/10.1016/j.isci.2025.112163

@article{fa5a91db11164111a9cf4a60e3db0c60,

title = "Targeting mTOR in myeloid cells prevents infection-associated inflammation",

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.",

keywords = "Biochemistry, Biological sciences, Immunology, Natural sciences",

author = "Toner, \{Yohana C.\} and Jazz Munitz and Geoffrey Prevot and Judit Morla-Folch and William Wang and \{van Elsas\}, Yuri and Bram Priem and Jeroen Deckers and Tom Anbergen and Beldman, \{Thijs J.\} and Brechb{\"u}hl, \{Eliane E.S.\} and Aksu, \{Muhammed D.\} and Athanasios Ziogas and Sarlea, \{Sebastian A.\} and Mumin Ozturk and Zhenhua Zhang and Wenchao Li and Yang Li and Alexander Maier and Fernandes, \{Jessica C.\} and Cremers, \{Glenn A.O.\} and \{van Genabeek\}, Bas and Kreijtz, \{Joost H.C.M.\} and Esther Lutgens and Riksen, \{Niels P.\} and Janssen, \{Henk M.\} and S{\"o}ntjens, \{Serge H.M.\} and Hoeben, \{Freek J.M.\} and Ewelina Kluza and Gagandeep Singh and Giamarellos-Bourboulis, \{Evangelos J.\} and Michael Schotsaert and Rapha{\"e}l Duivenvoorden and \{van der Meel\}, Roy and Joosten, \{Leo A.B.\} and Lei Cai and Temel, \{Ryan E.\} and Fayad, \{Zahi A.\} and Mhlanga, \{Musa M.\} and \{van Leent\}, \{Mandy M.T.\} and Teunissen, \{Abraham J.P.\} and Netea, \{Mihai G.\} and Mulder, \{Willem J.M.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

day = "18",

doi = "10.1016/j.isci.2025.112163",

language = "English",

volume = "28",

number = "4",

}

Toner, YC, Munitz, J, Prevot, G, Morla-Folch, J, Wang, W, van Elsas, Y, Priem, B, Deckers, J, Anbergen, T, Beldman, TJ, Brechbühl, EES, Aksu, MD, Ziogas, A, Sarlea, SA, Ozturk, M, Zhang, Z, Li, W, Li, Y, Maier, A, Fernandes, JC, Cremers, GAO, van Genabeek, B, Kreijtz, JHCM, Lutgens, E, Riksen, NP, Janssen, HM, Söntjens, SHM, Hoeben, FJM, Kluza, E, Singh, G, Giamarellos-Bourboulis, EJ, Schotsaert, M, Duivenvoorden, R, van der Meel, R, Joosten, LAB, Cai, L , Temel, RE, Fayad, ZA, Mhlanga, MM, van Leent, MMT, Teunissen, AJP, Netea, MG & Mulder, WJM 2025, 'Targeting mTOR in myeloid cells prevents infection-associated inflammation', iScience, vol. 28, no. 4, 112163. https://doi.org/10.1016/j.isci.2025.112163

TY - JOUR

T1 - Targeting mTOR in myeloid cells prevents infection-associated inflammation

AU - Toner, Yohana C.

AU - Munitz, Jazz

AU - Prevot, Geoffrey

AU - Morla-Folch, Judit

AU - Wang, William

AU - van Elsas, Yuri

AU - Priem, Bram

AU - Deckers, Jeroen

AU - Anbergen, Tom

AU - Beldman, Thijs J.

AU - Brechbühl, Eliane E.S.

AU - Aksu, Muhammed D.

AU - Ziogas, Athanasios

AU - Sarlea, Sebastian A.

AU - Ozturk, Mumin

AU - Zhang, Zhenhua

AU - Li, Wenchao

AU - Li, Yang

AU - Maier, Alexander

AU - Fernandes, Jessica C.

AU - Cremers, Glenn A.O.

AU - van Genabeek, Bas

AU - Kreijtz, Joost H.C.M.

AU - Lutgens, Esther

AU - Riksen, Niels P.

AU - Janssen, Henk M.

AU - Söntjens, Serge H.M.

AU - Hoeben, Freek J.M.

AU - Kluza, Ewelina

AU - Singh, Gagandeep

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Schotsaert, Michael

AU - Duivenvoorden, Raphaël

AU - van der Meel, Roy

AU - Joosten, Leo A.B.

AU - Cai, Lei

AU - Temel, Ryan E.

AU - Fayad, Zahi A.

AU - Mhlanga, Musa M.

AU - van Leent, Mandy M.T.

AU - Teunissen, Abraham J.P.

AU - Netea, Mihai G.

AU - Mulder, Willem J.M.

PY - 2025/4/18

Y1 - 2025/4/18

N2 - 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.

AB - 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.

KW - Biochemistry

KW - Biological sciences

KW - Immunology

KW - Natural sciences

UR - https://www.scopus.com/pages/publications/105000100029

UR - https://www.scopus.com/pages/publications/105000100029#tab=citedBy

U2 - 10.1016/j.isci.2025.112163

DO - 10.1016/j.isci.2025.112163

M3 - Article

AN - SCOPUS:105000100029

SN - 2589-0042

VL - 28

JO - iScience

JF - iScience

IS - 4

M1 - 112163

ER -

Targeting mTOR in myeloid cells prevents infection-associated inflammation

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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