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

• Published in: Nature communications 2023-07, Vol.14 (1), p.4060-4060, Article 4060
• Main Authors: Sadhu, Srikanth, Dalal, Rajdeep, Dandotiya, Jyotsna, Binayke, Akshay, Singh, Virendra, Tripathy, Manas Ranjan, Das, Vinayaka, Goswami, Sandeep, Kumar, Shakti, Rizvi, Zaigham Abbas, Awasthi, Amit
• Format: Article
• Language: English
• Subjects: 13/1; 49/39; 49/88; 49/90; 49/91; 631/250/127/1213; 631/250/249/2510/9; 631/326/596/4130; 631/80/304; 64/110; 64/60; 82/51; 96/31; 96/63; ACE2; Alveoli; Angiotensin-Converting Enzyme 2; Animals; CD4 antigen; COVID-19; Cytokines; Disease control; Drug development; Forkhead protein; FOXO1 protein; Humanities and Social Sciences; Hypersensitivity; Infections; Inflammation; Inflammatory diseases; Interleukin 9; Interleukin-9 - genetics; Lymphocytes; Lymphocytes T; Mice; multidisciplinary; Respiratory tract; Respiratory tract diseases; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Transcription factors; Transgenic mice; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39815-5

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. Interleukin 9 (IL-9) is a cytokine that plays causative role in airway inflammation of both infectious and allergic origin. Here authors show in a mouse model of SARS-CoV-2 infection that IL-9, predominantly produced by helper T cells, plays a critical pathogenic role in COVID-19 via an inflammatory pathway involving the transcription factor Foxo1.