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 IL-13 was associated with the need for mechanical ventilation in 2 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 (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA 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 HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology.
Highlights
SARS-CoV-2, the infectious agent causing the ongoing global COVID-19 pandemic, is a virus that primarily infects the lower respiratory tract of hosts by gaining entry to cells via the receptor angiotensin converting enzyme 2 (ACE2) facilitated by the transmembrane receptor neuropilin-1 [1, 2]
Cytokines were measured in the plasma sample taken closest to the first positive COVID-19 quantitative PCR test (Supplemental Figure 1)
Cytokines were arranged by principal component 1 (PC1) from Figure 1B
Summary
SARS-CoV-2, the infectious agent causing the ongoing global COVID-19 pandemic, is a virus that primarily infects the lower respiratory tract of hosts by gaining entry to cells via the receptor angiotensin converting enzyme 2 (ACE2) facilitated by the transmembrane receptor neuropilin-1 [1, 2]. This inflammatory state was associated with end-organ damage and in some cases death [4, 5] While it remains unclear how the individual cytokines associated with this response may be involved in severe outcomes in patients, inflammation is thought to be a primary driver of later stages of this disease. In support of this hypothesis, the use of the anti-inflammatory steroid dexamethasone decreased mortality by 29% in patients with COVID-19 who required mechanical ventilation [6]
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