The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration

Hart, D.; Uddin, M. J.; Dodd, R. J.; Brovero, S. G.; Fleming, C.; Moreau, G. B.; Natale, N. R.; Mann, B. J.; Sutherland, T. E.; Allen, J. E.; Day, A. J.; Petri, W. A.

doi:10.1101/2025.10.13.682000

bioRxiv · 10.1101/2025.10.13.682000

The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration

Hart, D.·Uddin, M. J.·Dodd, R. J.·Brovero, S. G.·Fleming, C.·Moreau, G. B.·Natale, N. R.·Mann, B. J.·Sutherland, T. E.·Allen, J. E.·Day, A. J.·Petri, W. A.

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Abstract

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 for patients. The relationship between the extracellular matrix and the host immune response to infection is severely understudied. 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 in many parts of the body, including cartilage, skin, brain, and vitreous body. CD44 is the primary receptor for HA and is 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, treatment with a combination of two anti-CD44 monoclonal antibodies confers a significant survival benefit and reduces weight loss and clinical score of the mice on Day 4 post infection. We show that anti-CD44 treatment decreases many key cytokines and chemokines in the bronchoalveolar lavage fluid on Day 4. With flow cytometry, we show that anti-CD44 reduces the numbers of neutrophils in infected lungs. We also show through immunofluorescence that treatment with anti-CD44 antibodies reduces colocalization of HA and CD45 in lung sections, indicating that HAs interaction with immune cells contributes to pathology. Our findings demonstrate that disruption of HA-receptor interactions is a way to prevent inflammatory pathology in pulmonary infection.

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Hart, D., Uddin, M. J., Dodd, R. J., Brovero, S. G., Fleming, C., Moreau, G. B., Natale, N. R., Mann, B. J., Sutherland, T. E., Allen, J. E., Day, A. J., Petri, W. A.. 2025-10-14. The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration. https://doi.org/10.1101/2025.10.13.682000

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