IL-13 is a driver of COVID-19 severity

Abstract

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts.In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator.Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.Summary: IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization reduced disease and decreased lung hyaluronan deposition.Administration of IL-13 induced hyaluronan in the lung. Blockade of the hyaluronan receptor CD44 prevented mortality, highlighting a novel mechanism for IL-13-mediated hyaluronan synthesis in pulmonary pathology.

Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

“…Luminex-based cytokine detection was done early (8 h) and late (48 h) post-SARS-CoV-2 infection with and without EPs 7630 treatment (100 μg/ml). We detected pronounced production of pro-inflammatory cytokines, chemokines, and immunomodulating growth factors in SARS-CoV-2 infected Calu-3 cells, most of which are associated with COVID-19-induced cytokine storm ( Figure 6 , right panel: I, II, III, red bars) ( Cauchois et al, 2020 ; Donlan et al, 2021 ; Pang et al, 2021 ; Petrey et al, 2021 ; Sugiyama et al, 2021 ). During the course of infection, the concentration of all analyzed proteins increased at 48 h p. i., analogously to SARS-CoV-2 viral loads in Calu-3 cells ( Figure 1 ).…”

“…In line with previous reports, we detected the production of inflammatory cytokines and growth factors in SARS-CoV-2-infected Calu-3 epithelial lung cells ( Callahan et al, 2021 ; Islam et al, 2021 ). Of note, key inflammatory factors and drivers of COVID-19-induced cytokine storm were included in our analysis (IL-6, IL-8, IL-13, TNF-α, CXCL9, CXCL10, PDGF, VEGF-A, CD40L, IL1RA) and showed robust upregulation in infected Calu-3 cells (see Figure 6 for graphical overview and details) ( Cauchois et al, 2020 ; Donlan et al, 2021 ; Pang et al, 2021 ; Petrey et al, 2021 ; Sugiyama et al, 2021 ). Strikingly, EPs 7630 treatment significantly reduced the production of major pro-inflammatory factors in SARS-CoV-2 infected Calu-3 cells.…”

Cytokine Signature Associated With Disease Severity in COVID-19

“…The appearance of elevated IL-10 may not play an effective protective role, but suggest a latent immune effort to control cytokine storm, which are unfortunately too late (32). Studies have revealed that IL-13 is a driver of COVID-19 severity (33), and could disrupts type 2 pneumocyte stem cell activity (34). While IL-13 neutralization results in reduced disease and lung hyaluronan deposition.…”

COVID‐19 and skin diseases: results from a survey of 843 patients with atopic dermatitis, psoriasis, vitiligo and chronic urticaria

“…5 IL-13 levels are elevated in individuals with severe COVID-19, especially among patients who require mechanical ventilation. 6 This fact may explain the worsening of AD lesions reported by respondents with severe dyspnoea in our study.…”