Role of Hyaluronan in IL-13-mediated COVID-19 Pathology

Project Summary Introduction: IL-13 is elevated in patients with COVID-19, in mice infected with SARS-CoV-2 IL-13 neutralization improved survival and decreased pulmonary deposition of hyaluronan (HA), and in a clinical trial IL-13/IL-4 blockade during severe acute COVID-19 improved DLCO and/or 6 minute walk test at one year. Here, we will

determine in mice infected with SARS-CoV-2 how IL-13 is induced, impacts HA matrices and lung inflammation. Hypothesis: We hypothesize that IL-13 produced by ILC2s in the lung during COVID-19 induces a hyaluronan (HA) matrix that via HA receptors recruits inflammatory cells, resulting in severe COVID-19.

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

Investigators: The application is the product of over two years of collaboration between investigators at the University of Virginia (UVA) and the University of Manchester. At UVA MPI William Petri brings expertise as a virologist and physician-scientist, and Jie Sun expertise in pulmonary viral host defense. The University of

Manchester MPIs bring expertise in type 2 immunity (Judith Allen) and hyaluronan (Tony Day). Innovation: Original observations and hypotheses include: (i) IL-13 contributes to acute and long-term respiratory failure in COVID-19; (ii) that IL-13 does so in part by activating HA deposition and by regulating IL-6;

and (iii) HA recruits to the lungs inflammatory cells expressing HA receptor(s), that result in damage to the lung. Approach: Specific Aim 1 (UVA): Hypothesis: IL-13-mediated pathology is driven by IL-33 induction of ILC2s and increased IL-4Rα/IL-13Rα1 expression, upregulated by IL-6. In the COVID-19 mouse model we will explore the roles of IL-

33 in inducing IL-13, and the contribution and interaction of IL-13 with IL-6 in promoting inflammation. Specific Aim 2 (Manchester): Hypothesis: IL-13 induces a cross-linked inflammatory HA-heavy chain matrix (HC•HA) in the lung. In uninfected mice, we will test the role of IL-13 in activating HC•HA matrix formation.

Specific Aim 3 (UVA): Hypothesis: IL-13 acts via pathogenic HA matrix formation to increase cellular inflammation through HA receptors including CD44 and decrease lung function. The HC•HA network in the lungs of mice infected with SARS-CoV-2 with or without IL-13 inhibition will be compared to that induced by IL-13 in a

naïve mouse (from Aim 2), and the role of immune cells recruited to the HC•HA matrix will be determined. Environment: Bill Petri and Jie Sun at the University of Virginia work at the intersection of immunology and infection. At the University of Manchester, the Division of Immunology, Immunity to Infection and Respiratory

Medicine (Judith Allen) and the Division of Cell Matrix Biology & Regenerative Medicine (Tony Day) uniquely bring together type 2 immunity, hyaluronan in the extracellular matrix, and infection.