Introduction: We discovered that IL-13 is elevated in patients with COVID-19, promoted disease in a mouse model, and in a RCT showed that IL-13/IL-4 blockade with dupilumab (anti-IL4Ra mAb) reduced mortality in patients with COVID-19. IL-13 induces the deposition of the polysaccharide hyaluronan (HA) in the lungs, and inhibition of the HA receptor CD44 protects from SARS-CoV-2 disease. We are determining the mechanisms by which alarmins such as IL-33 initiate a type 2 immune response, how IL-13 is induced, and its impact on HA matrices and CD44-mediated inflammation and disease.

Hypothesis: We hypothesize that IL-13 produced by ILC2s in the lung during COVID-19 induces a hyaluronan (HA) matrix that via HA receptors (including CD44⁺) recruits inflammatory cells, resulting in respiratory failure.

Significance: Uncovering the mechanisms of IL-13-induced hyaluronan matrices and signaling in driving COVID-19 severity has the promise of novel therapeutic approaches directed at the IL-13 - hyaluronan pathway, as well as being of importance for other pulmonary diseases where hyaluronan is known to contribute.