Role of neutrophil subsets in severe COVID-19 with thrombotic complications – Neutrosets

SARS-CoV-2 infection is characterized by a range of symptoms including fever, cough, fatigue and myalgia in the majority of cases. More severe cases of COVID-19 show development of acute respiratory distress syndrome (ARDS) leading to mortality. A high number of patients with ARDS secondary to COVID-19 also developed life-threatening thrombotic complications. Increasing clinical data indicated that the neutrophil-to-lymphocyte ratio (NLR) is a powerful predictive and prognostic indicator for severe COVID-19. In an attempt to identify neutrophil surface markers that may help to predict severity of COVID-19 infection, we recently developed a multi-parametric neutrophil profiling strategy and revealed two new immature neutrophil subsets. These markers were significantly correlated with disease severity in general, and more particularly with thromboembolic events. Whether these new tools may help monitor COVID-19 patients and improve clinical care remains to be determined. To test the hypothesis of a virally-driven neutrophil profile that could be a good COVID patients’ disease-state indicator, we now propose to better characterize the neutrophil subsets in COVID-19 patients and how neutrophil dysregulation that results from an inappropriate functional differentiation, may lead to a critical clinical outcome with thrombotic complications. The proposed research program combines ex vivo analysis in patients and a study using a preclinical murine model of COVID-19. We will first provide a detailed molecular and cellular analysis of the neutrophil subsets in blood in both COVID-19 patients and controls using high-resolution single cell RNA sequencing (scRNAseq) analysis. We will confirm that the phenotype, the function and the dynamic of some neutrophil subsets is associated with COVID-19 and its complications in a murine model of Sars-Cov2 infection. The final ambition of the consortium is to propose drugs targeting neutrophil subsets fate and differentiation leading to inflammatory disorders. Globally, this research program is designed to better understand the role of neutrophil subsets in COVID-19 and to define therapeutic targets directed at facilitating inflammation resolution and improving COVID-19 complications.