Neutrophils and lymphopenia, an unknown axis in severe COVID-19 disease

Abstract

The Coronavirus Disease 2019 (COVID-19) is caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus that can mediate asymptomatic or fatal infections characterized by pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. Several studies have highlighted the importance of B and T lymphocytes, given that neutralizing antibodies and T cell responses are required for an effective immunity. In addition, other reports have described myeloid cells such as macrophages and monocytes play a major role in the immunity against SARS-CoV-2 as well as dysregulated pro-inflammatory signature that characterizes severe COVID-19. During COVID-19, neutrophils have been defined as a heterogeneous group of cells, functionally linked to severe inflammation and thrombosis triggered by degranulation and NETosis, but also to suppressive phenotypes. The physiological role of suppressive neutrophils during COVID-19 and their implications in severe disease have been poorly studied and is not well understood. Here, we discuss the current evidence regarding the role of neutrophils with suppressive properties such as granulocytic myeloid-derived suppressor cells (G-MDSCs) and their possible role in suppressing CD4+ and CD8+ T lymphocytes expansion and giving rise to lymphopenia in severe COVID-19 infection.

Fig 1. Neutrophils and G-MDSCs during COVID-19.

Based on the current evidence, we hypothesize that the limited expansion of G-MDSCs (green) compared with classical pro-inflammatory neutrophils (pink) during (A) mild COVID-19 would be beneficial for the development of a balanced antiviral response due to robust proliferation of CD4⁺ (blue) and CD8⁺ (orange) T lymphocytes. In contrast, during (B) severe COVID-19, we speculate that the enhanced expansion of suppressive neutrophils may strongly suppress T cell proliferation and function, dysregulating the antiviral immune response and promoting excessive organ injury and diminished survival. The factors that promote the expansion of suppressive neutrophils as well as the putative suppressive mechanisms employed by these cells still need to be elucidated, and, if confirmed, it would add a new perspective of how neutrophil activity is involved in severe COVID-19 not limited to the classical view in which (C) pro-inflammatory neutrophils contribute to injury and disease through degranulation, NETosis, and pro-inflammatory cytokine production. The figure presented in this manuscript was generated with BioRender.com. COVID-19, Coronavirus Disease 2019; G-MDSC, granulocytic myeloid-derived suppressor cell; IL-10, interleukin 10; iNOS, inducible nitric oxide synthase; PDL-1, programmed death-ligand 1; TGF-β, transforming growth factor beta.