The Role of Proteases in Epithelial Dysregulation in Fungal Sinusitis

The role of epithelial dysregulation is poorly understood in fungal sinusitis. We aimed to examine differential gene expression and quantify protease expression in sinonasal tissue from distinct patient cohorts, those with and without invasive fungal sinusitis (IFS). We hypothesized that abnormal epithelial integrity in the sinonasal mucosa of immunosuppressed IFS patients may allow for tissue invasion.

Bulk RNA sequencing was performed on tissue from eight patients from two cohorts: immunosuppressed patients with and without IFS. Evaluation of protein expression for select proteases and their inhibitors was performed on all sinonasal tissues using multiplex western blotting. To expand upon these findings, protein expression of proteases and their inhibitors was evaluated in sinonasal tissue from eight patients with non-invasive fungal sinusitis (fungal ball).

Bulk RNA sequencing identified 33 genes that were differentially regulated in immunosuppressed IFS tissue compared to those without IFS. Multiplex western blot revealed several proteases, including matrix metalloproteinases (MMPs), with increased expression in the immunosuppressed IFS cohort compared to the cohorts without IFS. Tissue inhibitors of MMPs (TIMPs) were proportionally lower in IFS patient tissue compared to the control cohorts, resulting in several abnormal IFS-related MMP/TIMP ratios. In the non-invasive fungal sinusitis cohort, unique MMP/TIMP ratios were dysregulated.

Several proteases with increased expression in immunosuppressed IFS patients may be responsible for both an appropriate immune response to the pathogen as well as epithelial barrier breakdown and subsequent fungal invasion.