PMID- 36045686 OWN - NLM STAT- MEDLINE DCOM- 20220908 LR - 20231105 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - A novel virotherapy encoding human interleukin-7 improves ex vivo T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19. PG - 939899 LID - 10.3389/fimmu.2022.939899 [doi] LID - 939899 AB - 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-gamma (IFN-gamma) and/or Tumor necrosis factor-alpha (TNF-alpha) 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. CI - Copyright (c) 2022 Crausaz, Monneret, Conti, Lukaszewicz, Marchand, Martin, Inchauspe and Venet. FAU - Crausaz, Morgane AU - Crausaz M AD - Department of Infectious Diseases, Transgene SA, Lyon, France. AD - EA 7426 Pathophysiology of injury-induced immunosuppression (PI3), Lyon 1 University/Hospices Civils de Lyon/bioMerieux, Hopital Edouard Herriot, Lyon, France. FAU - Monneret, Guillaume AU - Monneret G AD - EA 7426 Pathophysiology of injury-induced immunosuppression (PI3), Lyon 1 University/Hospices Civils de Lyon/bioMerieux, Hopital Edouard Herriot, Lyon, France. AD - Hospices Civils de Lyon, Hopital Edouard Herriot, Laboratoire d'Immunologie, Lyon, France. FAU - Conti, Filippo AU - Conti F AD - EA 7426 Pathophysiology of injury-induced immunosuppression (PI3), Lyon 1 University/Hospices Civils de Lyon/bioMerieux, Hopital Edouard Herriot, Lyon, France. FAU - Lukaszewicz, Anne-Claire AU - Lukaszewicz AC AD - EA 7426 Pathophysiology of injury-induced immunosuppression (PI3), Lyon 1 University/Hospices Civils de Lyon/bioMerieux, Hopital Edouard Herriot, Lyon, France. AD - Hospices Civils de Lyon, Hopital Edouard Herriot, Service d'anesthesie-reanimation, Lyon, France. FAU - Marchand, Jean-Baptiste AU - Marchand JB AD - Department of Vectorology, Transgene SA, Illkirch-Graffenstraden, France. FAU - Martin, Perrine AU - Martin P AD - Department of Infectious Diseases, Transgene SA, Lyon, France. FAU - Inchauspe, Genevieve AU - Inchauspe G AD - Department of Infectious Diseases, Transgene SA, Lyon, France. FAU - Venet, Fabienne AU - Venet F AD - Hospices Civils de Lyon, Hopital Edouard Herriot, Laboratoire d'Immunologie, Lyon, France. AD - Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Universite Claude Bernard-Lyon 1, Lyon, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220815 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Cytokines) RN - 0 (Interleukin-7) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (STAT5 Transcription Factor) SB - IM MH - Animals MH - *COVID-19/therapy MH - Critical Illness MH - Cytokines/metabolism MH - Humans MH - Interleukin-7/metabolism MH - Mice MH - Receptors, Antigen, T-Cell/metabolism MH - STAT5 Transcription Factor/metabolism MH - *Sepsis/therapy MH - *Shock, Septic PMC - PMC9422896 OTO - NOTNLM OT - COVID-19 OT - T lymphocytes OT - immunostimulation OT - interleukin-7 OT - modified virus Ankara OT - sepsis OT - virotherapy COIS- MC, J-BM, PM, and GI were employees of Transgene SA when the work was performed. Transgene SA is a publicly traded French biopharmaceutical company, with Institut Merieux as the major shareholder. MC, GM, FC and A-CL work at EA7426, a joint unit including University, Hospital and bioMerieux, but are not employed by bioMerieux. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received f​​​​unding from Transgene SA. The funder had the following involvement with the study: collection of data, analysis, interpretation of data and writing of the article. EDAT- 2022/09/02 06:00 MHDA- 2022/09/09 06:00 PMCR- 2022/08/15 CRDT- 2022/09/01 02:15 PHST- 2022/05/09 00:00 [received] PHST- 2022/07/19 00:00 [accepted] PHST- 2022/09/01 02:15 [entrez] PHST- 2022/09/02 06:00 [pubmed] PHST- 2022/09/09 06:00 [medline] PHST- 2022/08/15 00:00 [pmc-release] AID - 10.3389/fimmu.2022.939899 [doi] PST - epublish SO - Front Immunol. 2022 Aug 15;13:939899. doi: 10.3389/fimmu.2022.939899. eCollection 2022.