Longitudinal immunological analyses reveal inflammatory misfiring in severe COVID-19 patients

Abstract

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in T cell number. We identify an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. Unsupervised clustering analysis of plasma and peripheral blood leukocyte data identified 4 immune signatures, representing (A) growth factors, (B) type-2/3 cytokines, (C) mixed type-1/2/3 cytokines, and (D) chemokines that correlated with three distinct disease trajectories of patients. The immune profile of patients who recovered with moderate disease was enriched in tissue reparative growth factor signature (A), while the profile for those with worsened disease trajectory had elevated levels of all four signatures. Thus, we identified development of a maladapted immune response profile associated with severe COVID-19 outcome and early immune signatures that correlate with divergent disease trajectories.

DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

“…Indeed, there are a number of clinical trials focused on the use of interferon and anti-inflammatory agents to counteract the sometimes deleterious immune response to SARS-CoV-2 infection (Angka et al, 2020). Such an approach could be key in treating severe cases of COVID-19, which correlate with cytokine storm and hyper-activation of immune responses normally not related to viral infections, particularly type-2 effectors (Lucas et al 2020). However, indiscriminate tempering of immune signaling would be counterproductive in the early stages of the infection and for patients with moderate disease, who appear to maintain a functional, well-adapted immune response.…”

“…As an example, the D614G mutation, which increases virulence, has been reported as potentially increasing glycosylation at neighboring asparagine 616 (Brufsky and Lotze, 2020;Jia et al, 2020;Korber et al, 2020). A recent proteomic profiling study pointed to DC-SIGN as a mediator of genetic risk in COVID-19 (Katz et al, 2020) and finally it is of note that DC/L-SIGN expression is induced by proinflammatory cytokines such as IL-4, IL-6, IL-10 and IL-13, known to be overexpressed in severe SARS and COVID-19 cases (Lucas et al, 2020;Relloso and Puig-Kroger). These observations prompted us to investigate the potential interaction of C-type lectins receptors, notably DC/L-SIGN with SARS-CoV-2, through glycan recognition of the spike envelope glycoprotein, as well at their potential role in SARS-CoV-2 transmission.…”

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

“…It is likely that differential expression in distinct cell types may account for the disparity of Egr-1 and its target gene expression in healthy controls and COVID-19 patients. Longitudinal studies in COVID-19 patients revealed that cytokines and chemokines were dramatically elevated in the lungs and correlated with the severity of the disease(57). Egr-1 mRNA levels were elevated and correlated with TNFSF10/TRAIL expression in the adult but not developing neutrophils of the peripheral blood mononuclear cells of COVID-19 patients compared with healthy controls(Figure 15).…”

“…(15,63,64). Recent studies have demonstrated dramatic changes in type I interferon, TNF-α, and IL-1 β production by immune cells and cytokine-mediated lung inflammation in COVID-19 patients(30,57,65,66). However, the role of Egr-1 in innate immunity and antiviral response to respiratory viruses in general and SARS-CoV-2, in particular, remains to be investigated.Transcriptional factor profiling in the transcriptome revealed that Egr-1was induced by IFN-α/β , TLR ligands, and TNF-α in human and mouse cells.…”

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

“…Development of Th1-polarized responses is also a feature of SARS-CoV2 in humans 13 . Moreover, severe COVID-19 is accompanied by prolonged and exacerbated Th1 responses 14 , which are suspected to contribute towards the observed pathogenic hyper-inflammation. We therefore focused our analyses of the scRNAseq datasets on CD4 + T cells.…”