The Pathogenic Role of IL-33 in the SARS-CoV-2-Infected Lung

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a significant threat to global public health. Pulmonary immunopathological damage plays a role in driving pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure in severe COVID-19. Therefore, dissecting the pulmonary immune response to SARS-CoV-2 infection is critical to under- stand disease pathogenesis and develop more effective therapeutics. Targeting of type 2 immune pathways is a potential avenue of therapeutic intervention in severe COVID-19. In particular, research has demonstrated a link between the type 2 cytokine IL-13 and COVID-19 severity. This proposal builds on the preliminary experi- ments demonstrating that blockade of the alarmin cytokine IL-33 confers protection in a mouse model of COVID- 19. IL-33 is a potent inducer of type 2 immunity in the lung, as its receptor ST2 is constitutively expressed by type 2 cells including type 2 innate lymphoid cells (ILC2s). It is hypothesized that IL-33/ST2 signaling induces a pathogenic inflammatory environment in the acutely infected lung by activating IL-13-secreting ILC2s and that IL-33-mediated inflammation enhances disruption of the respiratory epithelial barrier. To test this hypothesis, the impact of IL-33/ST2 signaling axis blockade on the inflammatory environment in the acutely infected lung will be described through assessment of the immune cell populations and the transcriptional profile of the respiratory epithelium (Aim 1). Considering that SARS-CoV-2-mediated ARDS is characterized by pulmonary inflammation and respiratory epithelial barrier disruption, these descriptive studies will elucidate pathways through which IL- 33 may drive pathogenesis. Further, the mechanism through which the IL-33/ST2 signaling axis drives patho- genesis will be directly tested (Aim 2). Mouse models of ILC2 depletion, selective ST2 knockout in ILC2s, and adoptive ILC2 transfer will be used to test whether IL-33-activated ILC2s drive pulmonary pathogenesis in the context of acute SARS-CoV-2 infection. Collectively, the proposed experiments will determine the mechanism underlying IL-33-mediated pathogenesis. This research is significant because it will further our understanding of how modulation of type 2 immunity can serve as a novel and promising therapeutic strategy in the treatment of respiratory viral infection-induced pulmonary pathology.