Prof. Univ. Dr. Iulia Popescu
Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent
Autori: Iulia Popescu, John F. McDyer
One Sentence Summary: Autocrine TNF-α/TNFRI regulates CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease.
Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFkB signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.
I am a Research Associate Professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, and I have significant experience in transplant research in basic immunology with a focus on mechanisms of CMV-specific lung mucosal/systemic immunity and viral control, as well on EBV, showing the important role for the Type-1 transcription factor T-bet and Eomes as well other immune markers. I also have experience in studying T cell mechanisms of allograft rejection/tolerance in lung transplantation. I am the Co-I on a U01 award (AI125050) to perform a novel clinical trial in tandem lung and bone marrow transplantation in select individuals with primary immunodeficiencies and end-stage lung disease, and to perform mechanistic pathogen-specific and alloimmune tolerance studies in these study participants. I am also a Co-I on an R01 award HL133184-01, “Role of F-box Proteins in Lung Transplantation.” In my study I’ve focused in viral mucosal immunology and I’m the Co-I on U01HL121814, “Immune Mechanisms of HIV-associated COPD. In addition, I’m the Co-I in another lung transplant research effort focused on novel drug development for antibody-mediated lung transplant rejection (Amgen). At the University of Pittsburgh site I’m Co-I for the R01, “Clinical Risk Factors in Primary Graft Dysfunction” (HL087115). I am proficient in measuring lung mucosal and systemic viral-specific and allospecific multifunctional T cell immunity and phenotyping in lung transplant recipients. I have helped in the establishment of an extensive lung transplant tissue biorepository/registry (BREATHE-LT) that collects and stores BAL fluid/cells, blood for plasma/PBMC, bronchial brushes, along with a clinical research database for phenotyping lung transplant recipients and assessing outcomes for translational studies. I am also working as a Co-PI on a current CFF award, “Molecular and Clinical Endotypes in Chronic Lung Allograft Dysfunction” in which RNA sequence analysis of the airway transcriptome and proteomics in ongoing studies in the mechanisms of CLAD. Finally, we have recently reported on the impact of short telomeres in pulmonary fibrosis lung transplant recipients who demonstrate increased CMV complications and impaired viral immunity. Pertinent to this proposal, recently I’m Co-I working with Dr. McDyer and Dr. Callaway in performing the ELISA assay to determine SARS CoV-2 Spike protein titers and SARS CoV-2 neutralization assay titers to assess convalescent plasma units and the impact of convalescent plasma therapy in participants in this SIREN Network clinical trial.
Positions and Employment
2020-pres Research Associate Professor, Pulmonary, Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
2014-2020. Research Assistant Professor, Pulmonary, Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
2012-2014 Research Associate/Manager Flow Cytometry Core, Pulmonary, Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
2010-2011 Senior Scientist/Technical Application Specialist, Cellular Technology Limited, Shaker Heights, OH
2006-2010 Faculty Research Instructor, Dept of Surgery Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
2001-2006 Postdoctoral Research Associate, Dept of Surgery Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
2000-2001 Research Scientist, Dept. of Cellular Immunology and Signal Transduction, Center of Immunology, Institute of Virology Bucharest, Romania
1997- 2000 Junior Research Scientist, Department Clinical Immunology, Center for Immunology, Bucharest, Romania
1997 3 months-Visiting Research PhD, Doctoral Scientist, Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
1994-1997 Research Associate – Dept. of Cellular Immunology and Signal Transduction, Center of Immunology, Institute of Virology, Bucharest, Romania
1991-1994 Resident Scientist- Department Clinical Immunology, Center for Immunology, Bucharest, Romania
Member – American Society of Transplantation (AST) 2006-present
Member – American Immunology Association (AIA) 2007-present
Member – European Association for Cancer Research (EACR) 1998-present
Member – Federation of European Biochemical Societies (FEBS) 1990-present
Member – Romanian Society of Immunology (SNI) 1986-present
Member – International Society of Heart and Lung Transplantation 2019-present