Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1β, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.

The ZEBRA (Z EBV replication activator) protein is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. An increasing body of studies have highlighted the critical role of EBV lytic infection as a risk factor for lymphoproliferative disorders, such as post-transplant lymphoproliferative disease (PTLD). We studied 108 transplanted patients (17 PTLD and 91 controls), retrospectively selected from different hospitals in France and in the Netherlands. The majority of PTLD were EBV-positive diffuse large B-cell lymphomas, five patients experienced atypical PTLD forms (EBV-negative lymphomas, Hodgkin’s lymphomas, and T-cell lymphomas). Fourteen patients among the seventeen who developed a pathologically confirmed PTLD were sZEBRA positive (soluble ZEBRA, plasma level above 20 ng/mL, measured by an ELISA test). The specificity and positive predictive value (PPV) of the sZEBRA detection in plasma were 98% and 85%, respectively. Considering a positivity threshold of 20 ng/mL, the sensitivity of the sZEBRA was 82.35% and the specificity was 94.51%. The mean of the sZEBRA values in the PTLD cases were significantly higher than in the controls (p < 0.0001). The relevance of the lytic cycle and, particularly, the role of ZEBRA in lymphomagenesis is a new paradigm pertaining to the prevention and treatment strategies for PTLD. Given the high-specificity and the predictive values of this test, it now appears relevant to investigate the lytic EBV infection in transplanted patients as a prognostic biomarker.