Calprotectin involvement in emergency hematopoiesis observed in severe COVID-19 – CALPRO

We have shown recently that patients with severe COVID-19 accumulate abnormal innate immune cells, including immature CD10low CD101- CXCR4+/- neutrophils and HLA-DRlow monocytes, in their blood and lungs (Silvin A et al, Cell 2020). We detected also the early disappearance of non-classical CD14low CD16+ monocytes and the release of massive amounts of the S100A8/S100A9 heterodimer, also known as calprotectin, as hallmarks of severe COVID-19. Elevation of peripheral blood calprotectin level was confirmed by several independent groups to predict high risk of severe outcome in SARS-CoV-2-infected patients. Several of these markers can be implemented in routine biology to detect earlier at risk patient who may evolve into severe and frequently lethal disease.

COVID-19-related death was associated with predisposing factors, including elevated age and a variety of comorbidities. Among cancer patients, the most fragile are those with a recent history of hematological malignancy who demonstrate a 2.5-fold increased risk of dying from severe COVID-9.

While our data established a correlation between high levels of circulating calprotectin and an emergency hematopoiesis generating immunosuppressive myeloid cells in severe COVID-19 patients, the contribution of S100A8/S100A9 to the initiation and support of stress hematopoiesis remains unclear. The proposed project aims to further explore the pathophysiological mechanisms involved in the emergency hematopoiesis detected in severe COVID-19 patients and to explore the behavior of clonal hematopoietic stem and progenitor cells (HSPCs) collected from patients with a myeloid malignancy in response to calprotectin.

Our hypothesis is that these malignant stem cells may demonstrate an enhanced ability to generate dysplastic innate immune cells and pro-thrombotic megakaryocytes in response to calprotectin.

We will determine the ability of calprotectin to induce an immunosuppressive and pro-thrombotic myeloid program at the HSPC level, and identify the receptor(s) involved in this effect. Identifying the calprotectin effects and the receptor(s) involved at the HSPC level may suggest therapeutic approaches to control the toxic feedback loop between mature and immature cells of the hematopoietic tissue that takes place in severe COVID-19.