Emergence of dysfunctional neutrophils with a defect in arginase-1 release in severe COVID-19

Dwivedi, A. and Mhaonaigh, A.U. and Carroll, M. and Khosravi, B. and Batten, I. and Ballantine, R.S. and Phelan, S.H. and O’Doherty, L. and George, A.M. and Sui, J. and Hawerkamp, H.C. and Fallon, P.G. and Noppe, E. and Mason, S. and Conlon, N. and Cheallaigh, C.N. and Finlay, C.M. and Little, M.A., Emergence of dysfunctional neutrophils with a defect in arginase-1 release in severe COVID-19, JCI Insight, 9, 17, 2024

Abstract

Neutrophilia occurs in patients infected with SARS-CoV-2 (COVID-19) and is predictive of poor outcomes. Here, we link heterogenous neutrophil populations to disease severity in COVID-19. We identified neutrophils with features of cellular aging and immunosuppressive capacity in mild COVID-19 and features of neutrophil immaturity and activation in severe disease. The low- density neutrophil (LDN) number in circulating blood correlated with COVID-19 severity. Many of the divergent neutrophil phenotypes in COVID-19 were overrepresented in the LDN fraction and were less detectable in normal-density neutrophils. Functionally, neutrophils from patients with severe COVID-19 displayed defects in neutrophil extracellular trap formation and reactive oxygen species production. Soluble factors secreted by neutrophils from these patients inhibited T cell proliferation. Neutrophils from patients with severe COVID-19 had increased expression of arginase-1 protein, a feature that was retained in convalescent patients. Despite this increase in intracellular expression, there was a reduction in arginase-1 release by neutrophils into serum and culture supernatants. Furthermore, neutrophil-mediated T cell suppression was independent of arginase-1. Our results indicate the presence of dysfunctional, activated, and immature neutrophils in severe COVID-19.