A prolonged innate systemic immune response in COVID-19

Abstract

Despite the introduction of vaccines, COVID-19 still affects millions of people worldwide. A better understanding of pathophysiology and the discovery of novel therapies are needed. One of the cells of interest in COVID-19 is the neutrophil. This cell type is being recruited to a site of inflammation as one of the first immune cells. In this project, we investigated a variety of neutrophils phenotypes during COVID-19 by measuring the expression of markers for migration, maturity, activation, gelatinase granules and secondary granules using flow cytometry. We show that neutrophils during COVID-19 exhibit altered phenotypes compared to healthy individuals. The activation level including NETs production and maturity of neutrophils seem to last longer during COVID-19 than expected for innate immunity. Neutrophils as one of the drivers of severe cases of COVID-19 are considered as potential treatment targets. However, for a successful implementation of treatment, there is a need for a better understanding of neutrophil functions and phenotypes in COVID-19. Our study answers some of those questions.

Increased IL-26 associates with markers of hyperinflammation and tissue damage in patients with acute COVID-19

“…The concentration of IL-26 in plasma was significantly increased in the COVID-19 group compared to the Control group (Figure 1A). Previously, we had shown that the plasma concentrations of IL-6, IL-8, and TNFa were similarly increased in this patient material (8). To better understand the relationship between IL-26 and these other cytokines, we now performed correlation analyses and found that the concentration of IL-26 displayed a strong positive correlation (r = 0.73) with that of IL-8 (Figure 1B), and a modest positive correlation (r = 0.39) with that of TNFa (Figure 1C), in the COVID-19 group.…”

“…Because IL-26 can bind and enhance the inflammatory potential of extracellular DNA (27), we characterized the relationship between the plasma concentration of IL-26 and markers of NET formation in the COVID-19 and Control groups. Notably, we and others have previously shown that NETs are increased in blood from COVID-19 patients (8,9). Indeed, in the current study, we found that the plasma concentration of IL-26 correlates with those of doublestranded DNA (dsDNA) and cell-free nucleosomes when the COVID-19 and Control groups were pooled together for analysis (Figures 3A, B).…”

“…The plasma concentration of TNFa correlated with the surface expression of CD47 when the COVID-19 and Control groups were pooled for analysis, whereas the concentration of IL-6 in plasma did not correlate with CD47 expression in any group (Supplementary Figures 3A, B). Moreover, we have recently shown that blood neutrophils isolated from the COVID-19 group have increased markers of activation (i.e., CD11b and CD66b) and a reduced surface expression of the maturity/migration marker CD49d (8). In the present study, we found that although the concentration of IL-26 did not correlate with the surface expression of CD11b in any group, it correlated with the surface expression of CD66b and the percentage of CD49d + neutrophils when the COVID-19 and Control groups were pooled for analysis (Supplementary Figures 4A-C).…”

“…Although neutrophils may contribute to viral clearance via cytokine release, phagocytosis, and production of extracellular traps (NETs), a growing body of evidence indicates that excessive neutrophil mobilization becomes pathogenic in COVID-19 (7). Along these lines, we and others recently demonstrated that blood neutrophils from patients with COVID-19 are hyperactivated and display enhanced survival and migration (6,8). In addition, this excessive neutrophil mobilization has been confirmed by the increased markers of NET production found in blood from patients with acute COVID-19 (8,9).…”

Relationship between red blood cell aggregation and dextran molecular mass

“…There is a strong link between the aggregation of RBCs and thrombosis 2,51,52 . Many studies have shown increased peripheral blood neutrophil activation with excessive development of Neutrophil Extracellular Traps (NETs) in COVID-19 patients due to aberrant immune response and higher virus replication [53][54][55][56] . It has been investigated that chlorine compounds produced by activated neutrophils in viral or bacterial infection lead to oxidative modification of albumin and the formation of AOPPs 57,58 .…”