The Role of Hyaluronan During Acute SARS-CoV-2 Infection 124 views

The novel respiratory disease COVID-19 caused by the coronavirus SARS-CoV-2 continues to be a public health emergency worldwide, and there is a need for more effective therapy. The relationship between the extracellular matrix and the host immune response to infection is severely understudied. We set out to understand how the extracellular matrix affects the host immune response to COVID-19. Deposition of the polysaccharide hyaluronan (HA) into the lungs is associated with more severe COVID-19 disease outcomes. HA is a major component of the extracellular matrix in connective tissues and is abundant throughout the body. HA polymers are synthesized by hyaluronan synthase (HAS) enzymes and interact with CD44, the primary receptor for HA found on almost all immune cells in the lung. Known functions of CD44 include mediation of immune cell migration, activation, and differentiation. We hypothesized that increased HA deposition during COVID-19 increases CD44-mediated immune cell infiltration into lungs and results in more severe pathology. Here, we report that in mice infected with a mouse-adapted strain of SARS-CoV-2, a combination treatment of two anti-CD44 monoclonal antibodies confers a significant survival benefit and reduces weight loss and clinical score following infection. This benefit is associated with decreased IL-6 and a reduction in neutrophil numbers in infected lungs. We also reveal through immunofluorescence that treatment with anti-CD44 antibodies reduces colocalization of HA and CD45 in lung sections, suggesting that HA’s interaction with immune cells contributes to pathology. In addition, blockade of the secondary HA receptor LYVE-1 that is primarily expressed on the lymphatic endothelium and macrophages is also protective against death due to SARS-CoV-2 infection and prevents HA binding to immune cells. We interrupted HA synthesis pharmacologically and genetically and found that neither approach completely reduced HA synthesis in the lung following infection, with preliminary findings suggesting modest protective effects. Finally, we interrupted HA cross-linking via TSG-6 knockout and showed that this may improve COVID-19 pathology. Our findings demonstrate that disruption of HA-receptor interactions is a way to prevent inflammatory pathology in pulmonary infection by SARS-CoV-2.

PHD (Doctor of Philosophy)

COVID-19; Immunology; Hyaluronan; SARS-CoV-2

English

2026-06-12