Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection

Brune, J.; Chang, M.; Tang, F.; Lopez-Martinez, C.; Reeves, S.; Chan, C.; Waldron, P.; Boyd, D. F.; Gharib, S. A.; Thomas, P.; Altemeier, W. A.; Frevert, C.

doi:10.1101/2025.08.01.668194

bioRxiv · 10.1101/2025.08.01.668194

Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection

Brune, J.·Chang, M.·Tang, F.·Lopez-Martinez, C.·Reeves, S.·Chan, C.·Waldron, P.·Boyd, D. F.·Gharib, S. A.·Thomas, P.·Altemeier, W. A.·Frevert, C.

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Abstract

Viral and bacterial lung infections place a significant burden on public health. Versican, an extracellular matrix (ECM) chondroitin sulfate proteoglycan, coordinates the innate immune response in multiple experimental models. Versicans potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling the hosts immune response to lung infection. However, versicans contribution to lung inflammation, injury, and immune cell activity during influenza A virus (IAV) infection represents a critical knowledge gap. To address our central hypothesis that mesenchymal-derived versican is pro-inflammatory and enhances the innate immune response to IAV infection, we generated a tamoxifen-inducible mouse deficient in mesenchymal-derived versican (B6. Col1a2-CreERT+/-/Vcantm1.1Cwf, Col1a2/Vcan-/-). We report that mesenchymal-derived versican plays a critical role in neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in IAV infection. Intriguingly, mesenchymal-derived versican deficiency had the most substantial negative impact on neutrophil emigration into the lungs. We found that neutrophils were less adhesive to the ECM of Col1a2/Vcan-/- mouse lung fibroblasts (mLFs), which had a significant decrease in versican compared to wild-type mLFs. Additionally, Col1a2/Vcan-/- mLFs treated with poly(I:C) in vitro have reduced cell-associated hyaluronan. These findings suggest that fibroblast-derived versican is necessary for adhesion to lung fibroblasts by neutrophils as they transit into the lung interstitium and airways from the pulmonary vasculature. Our findings demonstrate that mesenchymal-derived versican is a key regulator of the early host immune responses to IAV. NEW & NOTEWORTHYWe report the novel finding that mesenchymal-derived versican is critical for neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in influenza A virus infection. Additionally, a differentiated neutrophil-cell line is less adherent to versican-deficient fibroblasts, and versican-deficient fibroblasts have significantly reduced cell-associated hyaluronan (HA) content in vitro. These findings suggest that mesenchymal-derived versican and cell-associated HA are necessary for the adhesion of neutrophils and monocytes to lung fibroblasts.

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Brune, J., Chang, M., Tang, F., Lopez-Martinez, C., Reeves, S., Chan, C., Waldron, P., Boyd, D. F., Gharib, S. A., Thomas, P., Altemeier, W. A., Frevert, C.. 2025-08-02. Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection. https://doi.org/10.1101/2025.08.01.668194

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