IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo
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Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signaling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents. We investigated the role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo. IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2- expressing ciliated cells rather than by neutralization in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened disease severity in mice; the effects were mediated by eicosanoid signaling and were abolished in mice deficient in the phospholipase A2 enzyme PLA2G2D. We conclude that IL-13-induced inflammation differentially affects multiple steps of COVID-19 pathogenesis. IL-13-induced inflammation may be protective against initial SARS-CoV-2 airway epithelial infection; however, it enhances disease progression in vivo. Blockade of IL-13 and/or eicosanoid signaling may be protective against progression to severe respiratory virus-induced lung disease.
RESEARCH IN CONTEXT
Evidence before this study
Prior to this study, various pieces of evidence indicated the significant role of cytokines in the pathogenesis and progression of COVID-19. Severe COVID-19 cases were marked by cytokine storm syndrome, leading to immune activation and hyperinflammation. Treatments aimed at modulating cytokine signaling, such as IL-6 receptor antagonists, had shown moderate effects in managing severe COVID-19 cases. Studies also revealed an excessive production of type 2 cytokines, particularly IL-13 and IL-4, in the plasma and lungs of COVID-19 patients, which was associated with adverse outcomes. Treatment with anti-IL-13 monoclonal antibodies improved survival following SARS-CoV-2 infection, suggesting that IL-13 plays a role in disease severity. Type 2 cytokines were observed to potentially suppress type 1 responses, essential for viral clearance, and imbalances between these cytokine types were linked to negative COVID-19 outcomes. These findings highlighted the complex interactions between cytokines and the immune response during viral infections, underscoring the importance of understanding IL-13’s role in COVID-19 and related lung diseases for developing effective therapeutic interventions.
Added value of this study
In this study, we explored the impact of IL-13-induced inflammation on various stages of the SARS-CoV-2 infection cycle using both murine (in vivo) and primary human airway epithelial (in vitro) culture models. Our findings indicated that IL-13 provided protection to airway epithelial cells against SARS-CoV-2 infection in vitro, partly by reducing the number of ACE2- expressing ciliated cells. Conversely, IL-13 exacerbated the severity of SARS2-N501Y MA30 -induced disease in mice, primarily through Pla2g2d-mediated eicosanoid biosynthesis.
Implications of the available evidence
Current evidence indicates that PLA 2 G2D plays a crucial role in the IL-13-driven exacerbation of COVID-19 in mice, suggesting that targeting the IL-13-PLA2G2D axis could help protect against SARS-CoV-2 infection. These insights are important for clinical research, especially for studies focusing on drugs that modify IL-13 signaling or modulate eicosanoids in the treatment of asthma and respiratory virus-induced lung diseases.
