The unbalanced p53/SIRT1 axis may impact lymphocyte homeostasis in COVID-19 patients

Bordoni, Veronica; Tartaglia, Eleonora; Sacchi, Alessandra; Fimia, Gian Maria; Cimini, Eleonora; Casetti, Rita; Notari, Stefania; Grassi, Germana; Marchioni, Luisa; Bibas, Michele; Capobianchi, Maria R.; Locatelli, Franco; Maeurer, Markus; Zumla, Alimuddin; Antinori, Andrea; Nicastri, Emanuele; Ippolito, Giuseppe; Agrati, Chiara

Background/Objectives Dysregulated inflammatory profile play an important role in COVID-19 pathogenesis. Moreover, depletion of lymphocytes is typically associated with an unfavorable 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 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 a higher concentrations of plasma proinflammatory cytokines (IL1β, TNF-α, IL8, IL6) than HD. Deacetylase Sirtuin 1 (SIRT1) expression was significantly decreased in COVID-19 patients, and was negatively correlated with p53 (p = 0.003 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 compared with HD. Reduction of IgK and IgL chains was seen in lymphopenic COVID-19 patients. A significant increase of both apoptotic B and T cells were observed. Inflammatory cytokines correlated positively with p53 (IL-1β: r = 0.5, p = 0.05;IL-8: r = 0.5, p = 0.05) and negatively with SIRT1 (IL1-β: r=-0.5,p = 0.04;TNF-α: r=-0.4, 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 SARS-COV2 infection.