IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation

Srikanth Sadhu, Rajdeep Dalal, Jyotsna Dandotiya, Akshay Binayke, Virendra Singh, Manas Ranjan Tripathy, Vinayaka Das, Sandeep Goswami, Shakti Kumar, Zaigham Abbas Rizvi and Amit Awasthi ()
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Srikanth Sadhu: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Rajdeep Dalal: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Jyotsna Dandotiya: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Akshay Binayke: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Virendra Singh: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Manas Ranjan Tripathy: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Vinayaka Das: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Sandeep Goswami: NCR-Biotech Science Cluster, 3rd Milestone
Shakti Kumar: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway
Zaigham Abbas Rizvi: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone
Amit Awasthi: Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract SARS-CoV-2 infection is known for causing broncho-alveolar inflammation. Interleukin 9 (IL-9) induces airway inflammation and bronchial hyper responsiveness in respiratory viral illnesses and allergic inflammation, however, IL-9 has not been assigned a pathologic role in COVID-19. Here we show, in a K18-hACE2 transgenic (ACE2.Tg) mouse model, that IL-9 contributes to and exacerbates viral spread and airway inflammation caused by SARS-CoV-2 infection. ACE2.Tg mice with CD4+ T cell-specific deficiency of the transcription factor Forkhead Box Protein O1 (Foxo1) produce significantly less IL-9 upon SARS-CoV-2 infection than the wild type controls and they are resistant to the severe inflammatory disease that characterises the control mice. Exogenous IL-9 increases airway inflammation in Foxo1-deficient mice, while IL-9 blockade reduces and suppresses airway inflammation in SARS-CoV-2 infection, providing further evidence for a Foxo1-Il-9 mediated Th cell-specific pathway playing a role in COVID-19. Collectively, our study provides mechanistic insight into an important inflammatory pathway in SARS-CoV-2 infection, and thus represents proof of principle for the development of host-directed therapeutics to mitigate disease severity.

Date: 2023
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DOI: 10.1038/s41467-023-39815-5

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