tetano
Editor, Senior Moderator
EBioMedicine
. 2025 Sep 15:120:105920.
doi: 10.1016/j.ebiom.2025.105920. Online ahead of print. IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling
Shreya Ghimire[SUP] 1 [/SUP], Biyun Xue[SUP] 1 [/SUP], Kun Li[SUP] 2 [/SUP], Ryan M Gannon[SUP] 1 [/SUP], Christine L Wohlford-Lenane[SUP] 2 [/SUP], Andrew L Thurman[SUP] 1 [/SUP], Huiyu Gong[SUP] 1 [/SUP], Grace C Necker[SUP] 1 [/SUP], Jian Zheng[SUP] 3 [/SUP], David K Meyerholz[SUP] 4 [/SUP], Stanley Perlman[SUP] 5 [/SUP], Paul B McCray Jr[SUP] 6 [/SUP], Alejandro A Pezzulo[SUP] 7 [/SUP]
Affiliations
Background: 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 signalling-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.
Methods: The role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response was investigated in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo using single-cell and bulk RNA-sequencing approaches. Additionally, the responses were quantified using immunofluorescence, histopathology, immunohistochemistry and LC-MS/MS assays.
Findings: 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 neutralisation 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 signalling and were abolished in mice deficient in the phospholipase A[SUB]2[/SUB] enzyme PLA2G2D.
Interpretation: 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 signalling may be protective against progression to severe respiratory virus-induced lung diseases.
Funding: Carver Trust COVID-19 Grant; CF Foundation Iowa RDP; NIH 1R01HL163024; K01HL140261; NIH R01AI129269; NIH P01AI060699; NIH Grant P30 DK-54759; Cystic Fibrosis Foundation PEZZUL20A1-KB; Stead Family Foundation.
Keywords: COVID-19; Eicosanoids; IL-13; Prostaglandin; SARS-CoV-2; scRNA-seq.
. 2025 Sep 15:120:105920.
doi: 10.1016/j.ebiom.2025.105920. Online ahead of print. IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling
Shreya Ghimire[SUP] 1 [/SUP], Biyun Xue[SUP] 1 [/SUP], Kun Li[SUP] 2 [/SUP], Ryan M Gannon[SUP] 1 [/SUP], Christine L Wohlford-Lenane[SUP] 2 [/SUP], Andrew L Thurman[SUP] 1 [/SUP], Huiyu Gong[SUP] 1 [/SUP], Grace C Necker[SUP] 1 [/SUP], Jian Zheng[SUP] 3 [/SUP], David K Meyerholz[SUP] 4 [/SUP], Stanley Perlman[SUP] 5 [/SUP], Paul B McCray Jr[SUP] 6 [/SUP], Alejandro A Pezzulo[SUP] 7 [/SUP]
Affiliations
- PMID: 40957220
- DOI: 10.1016/j.ebiom.2025.105920
Background: 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 signalling-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.
Methods: The role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response was investigated in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo using single-cell and bulk RNA-sequencing approaches. Additionally, the responses were quantified using immunofluorescence, histopathology, immunohistochemistry and LC-MS/MS assays.
Findings: 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 neutralisation 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 signalling and were abolished in mice deficient in the phospholipase A[SUB]2[/SUB] enzyme PLA2G2D.
Interpretation: 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 signalling may be protective against progression to severe respiratory virus-induced lung diseases.
Funding: Carver Trust COVID-19 Grant; CF Foundation Iowa RDP; NIH 1R01HL163024; K01HL140261; NIH R01AI129269; NIH P01AI060699; NIH Grant P30 DK-54759; Cystic Fibrosis Foundation PEZZUL20A1-KB; Stead Family Foundation.
Keywords: COVID-19; Eicosanoids; IL-13; Prostaglandin; SARS-CoV-2; scRNA-seq.