%0 Journal Article %T A novel virotherapy encoding human interleukin-7 improves ex vivo T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19 %+ Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3) %+ Transgene SA [Lyon] %+ Hôpital Edouard Herriot [CHU - HCL] %+ Transgene SA [Illkirch] %+ Centre International de Recherche en Infectiologie (CIRI) %A Crausaz, Morgane %A Monneret, Guillaume %A Conti, Filippo %A Lukaszewicz, Anne-Claire %A Marchand, Jean-Baptiste %A Martin, Perrine %A Inchauspé, Geneviève %A Venet, Fabienne %@ 1664-3224 %J Frontiers in Immunology %I Frontiers %V 13 %P 939899 %8 2022-08-15 %D 2022 %R 10.3389/fimmu.2022.939899 %M 36045686 %K interleukin-7 %K virotherapy %K modified virus Ankara %K T lymphocytes %K sepsis %K immunostimulation %K COVID-19 %Z Life Sciences [q-bio]Journal articles %X A majority of patients with sepsis surviving the first days in intensive care units (ICU) enter a state of immunosuppression contributing to their worsening. A novel virotherapy based on the non-propagative Modified Virus Ankara (MVA) expressing the human interleukin-7 (hIL-7) cytokine fused to an Fc fragment, MVA-hIL-7-Fc, was developed and shown to enhance innate and adaptive immunity and confer survival advantages in murine sepsis models. Here, we assessed the capacity of hIL-7-Fc produced by the MVA-hIL-7-Fc to improve ex vivo T lymphocyte functions from ICU patients with sepsis. Primary hepatocytes were transduced with the MVA-hIL-7-Fc or an empty MVA, and cell supernatants containing the secreted hIL-7-Fc were harvested for in vitro and ex vivo studies. Whole blood from ICU patients [septic shock = 15, coronavirus disease 2019 (COVID-19) = 30] and healthy donors (n = 36) was collected. STAT5 phosphorylation, cytokine production, and cell proliferation were assessed upon T cell receptor (TCR) stimulation in presence of MVA-hIL-7-Fc–infected cell supernatants. Cells infected by MVA-hIL-7-Fc produced a dimeric, glycosylated, and biologically active hIL-7-Fc. Cell supernatants containing the expressed hIL-7-Fc triggered the IL-7 pathway in T lymphocytes as evidenced by the increased STAT5 phosphorylation in CD3+ cells from patients and healthy donors. The secreted hIL-7-Fc improved Interferon-γ (IFN-γ) and/or Tumor necrosis factor-α (TNF-α) productions and CD4+ and CD8+ T lymphocyte proliferation after TCR stimulation in patients with bacterial and viral sepsis. This study demonstrates the capacity of the novel MVA-hIL-7-Fc–based virotherapy to restore ex vivo T cells immune functions in ICU patients with sepsis and COVID-19, further supporting its clinical development. %G English %2 https://inserm.hal.science/inserm-04010224/document %2 https://inserm.hal.science/inserm-04010224/file/fimmu-13-939899.pdf %L inserm-04010224 %U https://inserm.hal.science/inserm-04010224 %~ INSERM %~ UNIV-ST-ETIENNE %~ ENS-LYON %~ HCL %~ CNRS %~ UNIV-LYON1 %~ HEH %~ CIRI %~ UDL %~ UNIV-LYON