The unbalanced p53/SIRT1 axis may impact lymphocyte homeostasis in COVID-19 patients.
Veronica Bordoni, Eleonora Tartaglia, Alessandra Sacchi, Gian Maria Fimia, Eleonora Cimini, Rita Casetti, Stefania Notari, Germana Grassi, Luisa Marchioni, Michele Bibas, Maria R Capobianchi, Franco Locatelli, Markus Maeurer, Alimuddin Zumla, Andrea Antinori, Emanuele Nicastri, Giuseppe Ippolito, Chiara Agrati
Gian Maria Fimia: INMI Lazzaro Spallanzani-IRCCS, Via Portuense, 292, 00149 Rome, Italy; Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy.
Maria R Capobianchi: INMI Lazzaro Spallanzani-IRCCS, Via Portuense, 292, 00149 Rome, Italy.
Franco Locatelli: Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Markus Maeurer: Immunotherapy Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal; I Med Clinic, University of Mainz, Mainz, Germany.
Alimuddin Zumla: Division of Infection and Immunity, University College London, London, UK; National Institute or Health Research Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
Andrea Antinori: INMI Lazzaro Spallanzani-IRCCS, Via Portuense, 292, 00149 Rome, Italy.
BACKGROUND/OBJECTIVES: A dysregulated inflammatory profile plays an important role in coronavirus disease-2019 (COVID-19) pathogenesis. Moreover, the depletion of lymphocytes is typically associated with an unfavourable disease course. We studied the role and impact of p53 and deacetylase Sirtuin 1 (SIRT1) on lymph-monocyte homeostasis and their possible effect on T and B cell signalling. METHODS: Gene expression analysis and flow cytometry were performed on peripheral blood mononuclear cells (PBMC) of 35 COVID-19 patients and 10 healthy donors (HD). Inflammatory cytokines, the frequency of Annexin+ cells among CD3+ T cells and CD19+ B cell subsets were quantified. RESULTS: PBMC from COVID-19 patients had a higher p53 expression, and higher concentrations of plasma proinflammatory cytokines (IL1β, TNF-α, IL8, and IL6) than HD. Deacetylase Sirtuin 1 (SIRT1) expression was significantly decreased in COVID-19 patients and was negatively correlated with p53 (p = 0.003 and r = -0.48). A lower expression of IL-7R and B Cell linker (BLNK), key genes for lymphocyte homeostasis and function, was observed in COVID-19 than in HD. The reduction of IgK and IgL chains was seen in lymphopenic COVID-19 patients. A significant increase in both apoptotic B and T cells were observed. Inflammatory cytokines correlated positively with p53 (IL-1β: r = 0.5 and p = 0.05; IL-8: r = 0.5 and p = 0.05) and negatively with SIRT1 (IL1-β: r = -0.5 and p = 0.04; TNF-α: r = -0.4 and p = 0.04). CONCLUSIONS: Collectively, our data indicate that the inflammatory environment, the dysregulated p53/SIRT1 axis and low expression of IL7R and BLNK may impact cell survival, B cell signalling and antibody production in COVID-19 patients. Further studies are required to define the functional impact of low BLNK/IL7R expression during severe acute respiratory syndrome coronavirus-2 infection.
