Monocyte-Driven Atypical Cytokine Storm and Aberrant Neutrophil Activation as Key Mediators of COVID19 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.

Mapping the recovery of critically ill COVID19 patients by high-dimensional profiling identifies longitudinal blood immunotypes

“…To analyse the data, we continued using the FlowSOM models built for [12]. To generate these models, normalized .fcs les were rst transferred to the Maxpar Pathsetter™ software (version 2.0.45), which performs a standardized, automatic and unsupervised quality check (bead removal and high-quality singlet selection) and gating of live single cells.…”

“…Antigen-presentation by monocytes, pDCs and/or mDCs plays a vital role in the initiation of an e cient adaptive immune response to viral infections [37][38][39][40][41]. As previously shown, declined levels of HLA-DR expression and hence a reduced antigen presentation seems to be an early hallmark of a trajectory towards a severe COVID-19 disease course compared to a mild/moderate one [10,12]. Considering that monocytes are among the rst immune cell types to recover, we further investigated the functionality of these cells across the 4 NLR pro les during recovery.…”

“…Two patients were con rmed positive for SARS-CoV2 via CT scan. Routine clinical laboratory tests at the time of sampling were performed in line with the 'COntAGIous' study design [12]. The patients enrolled in the study were sampled at several relevant time points: upon admission to the ICU (0-2 days post admission), at 6 +/-2 days post admission, and eventually at ICU discharge.…”

“…The early phase of severe COVID19 is characterized by a functional shift towards a more immunosuppressive spectrum of monocytes, as seen by a downregulation of HLA-DR and an enrichment of CD163+ monocytes in R4 (Figure 3) [10,12]. However, longitudinal follow-up shows that this shift is reversible, as seen by the recovery of HLA-DR expression and a relative reduction of the amount of immunosuppressive CD163+ monocytes ( see Cl53 and Cl32; Figure 3C), leading to a regain of the antigen-presenting phenotype of these cells.…”

“…As such, it has been shown that COVID-19 leads to the combination of pathologically elevated levels of pro-in ammatory cytokines, coagulopathy and a dysregulated immune response [6,8,9]. Deep immune pro ling in severe COVID-19 patients revealed excessive amounts of dysfunctional neutrophils, decreased levels of lymphocytes and low levels of antigenpresenting receptors on monocytes and dendritic cells, hindering e cient adaptive immune responses [8,[10][11][12]. In contrast to asymptomatic or mild/moderate symptomatic COVID-19 patients, critically ill patients typically show a biphasic disease course with an early viral stage of disease before ICU admission, followed by an hypoxic phase of disease, characterized by a cytokine storm and an acute respiratory distress syndrome, requiring (invasive) respiratory support, antivirals and immune-modulation to prevent multiple organ failure and death Considering the potentially severe and unpredictable impact of a SARS-CoV2 infection, research has also focused on predicting the disease course of COVID-19.…”