Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity

Abstract

Epidemiological and clinical reports have indicated that the host immune response to SARS-CoV-2, more so than viral factors, determines COVID-19 disease severity. To elucidate the immunopathology underlying COVID-19 severity, cytokine and multiplex immune profiling was performed in mild-moderate and critically-ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, and was more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels followed by deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presenting machinery was reduced in critical disease, while also neutrophils contributed to disease severity and local tissue damage by amplifying hypercytokinemia and neutrophil extracellular trap formation. We suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

“…Likewise, Severe patients presented an elevated level of blood IL6 ( Figure S2A ). These results are consistent with the previously reported production of pro-inflammatory cytokines by monocytic cells in patients with severe disease (Hadjadj et al, 2020; Vanderbeke et al, 2021) , and provided further insights into the differential responses of other cells.…”

“…Overall, the patients experiencing mild infection demonstrated high IFN-I/λ blood levels at early time-points. Furthermore, the inflammatory response appeared to be correlated with disease severity, in agreement with previous reports (Galani et al, 2021; Hadjadj et al, 2020; McGonagle et al, 2020; Vanderbeke et al, 2021) .…”

“…Both approaches revealed an elevated IFN-I/λ response at early time points (within the first 10-11 days post-onset of symptoms) for all patients with mild symptoms, that seemed to vanish over time, mirroring the controlled decrease of the viral load ( Figure S2A and Table S1 ). Of note, the level of the pro- inflammatory cytokine IL6 was elevated in Severe patients ( Figure S2A and Table S1 ), in line with the previously reported production of pro-inflammatory cytokines in COVID-19 patients (McGonagle et al, 2020; Vanderbeke et al, 2021).…”

Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019

“…These observations are in line with the previously reported enhanced myeloperoxidase (MPO) levels in COVID-19 plasma. 25 A trend towards enhanced neutrophil , (e) CXCL8, (f) CXCL10 and (g) CXCL11 in plasma samples from COVID-19 patients who stayed at the ICU [samples were collected during the first 48 h after admission (ICUday 1; n ≥ 10), after one week (ICUday 7; n ≥ 10) and upon discharge from the ICU (ICUdischarge; n ≥ 10)], COVID-19 patients who were hospitalised in general wards (ward; n ≥ 13) and healthy controls (HC; n ≥ 7). Moreover, (h) CD26/DPP4 enzyme activity was determined in a substrate conversion assay.…”

ZBP1 induces inflammatory signaling via RIPK3 and promotes SARS-CoV-2-induced cytokine expression

“…In addition, analysis of a single-cell RNAsequencing dataset (Ren et al, 2021) showed that ZBP1 expression was significantly higher in COVID-19 patients in the progressive disease stage than those in the convalescent stage or healthy controls (Figure 7B). Monocytes and neutrophils have been found to be two major sources of cytokines in the peripheral blood that contribute to the "cytokine storm" in critically ill COVID-19 patients (Ren et al, 2021;Vanderbeke et al, 2021). Analysis of the single-cell RNAseq dataset (Ren et al, 2021) revealed an increase in ZBP1 expression in neutrophils and all major inflammatory subsets of monocytes in COVID-19 patients in progressive stage compared to convalescent stage patients (Figure S7A).…”