Spleen tyrosine kinase inhibition restores neutrophil homeostasis in COVID-19

Abstract Spleen tyrosine kinase (SYK) is a novel therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, SYK inhibitor, was studied phase 2 placebo-controlled randomized clinical trial associated with improvements many secondary end points related to efficacy. Here, we used multiomic approach evaluate cellular soluble immune mediator responses of patients enrolled this trial. We demonstrated inhibition reduced activation, increased circulation mature neutrophils (CD10+CD33−), decreased low-density granulocytes (LDG) polymorphonuclear myeloid-derived suppressor cells (HLA-DR–CD33+CD11b−). Additionally, LDG transcriptional profiles were distinct COVID-19 compared during autoimmune conditions. Together, these data suggest may mitigate proinflammatory thought contribute immunopathogenesis severe COVID-19. This work has been funded part by the Intramural Research Program NIH Clinical Center (NIHCC) including Award for Staff Clinicians (FY2020/FY2021), NHLBI, National Institute Allergy Infectious Diseases (NIAID), Arthritis Musculoskeletal Skin (NIAIMS)