The alarmin IL-33 exacerbates pulmonary inflammation and immune dysfunction in SARS-CoV-2 infection
Hui Wang,
Yashoda M. Hosakote,
Paul J. Boor,
Jun Yang,
Yuanyi Zhang,
Xiaoying Yu,
Casey Gonzales,
Corri B. Levine,
Susan McLellan,
Nicole Cloutier,
Xuping Xie,
Pei-Yong Shi,
Ping Ren,
Haitao Hu,
Keer Sun,
Lynn Soong,
Jiaren Sun,
Yuejin Liang
Affiliations
Hui Wang
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
Yashoda M. Hosakote
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Paul J. Boor
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Jun Yang
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
Yuanyi Zhang
Department of Biostatistics and Data Science, the University of Texas Medical Branch, Galveston, TX 77555, USA
Xiaoying Yu
Department of Biostatistics and Data Science, the University of Texas Medical Branch, Galveston, TX 77555, USA
Casey Gonzales
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Corri B. Levine
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
Susan McLellan
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
Nicole Cloutier
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
Xuping Xie
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
Pei-Yong Shi
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
Ping Ren
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Haitao Hu
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Keer Sun
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Lynn Soong
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Jiaren Sun
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Yuejin Liang
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Corresponding author
Summary: Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33−/− mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33−/− mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.
