Targeting mTOR in myeloid cells prevents infection-associated inflammation. iScience. 2025 Mar 4;28(4):112163.
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.
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.
doi: 10.1016/j.isci.2025.112163. PMID: 40177636; PMCID: PMC11964677.
