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Additional file 1: Figure S1. Distribution Analysis of NE Activity in WBCs Collected Over the Trial Duration. NE activity from WBCs is shown in a quantile-quantile plot of measured values versus predicted standard normal distribution values, in a distribution plot, and in a relative frequency histogram plot. The height of the outlined box in panel B indicates the mean value for each arm. Median values for WBC NE are 5772, 4947, 3392 and 4776 ng/mL for placebo, 10 mg brensocatib, 25 mg brensocatib and all arms combined, respectively. Figure S2. Distribution Analysis of Sputum NE Activity Collected Over the Trial Duration. NE activity in sputum is shown in a quantile-quantile plot of measured values versus predicted standard normal distribution values, in a distribution plot, and in a relative frequency histogram plot. The bar in panel B indicates the mean NE activity for each arm. Median activity values for each group in the analysis are 3.32, 2.21, 1.50 and 2.30 log (ng/mL) for sputum NE for placebo, 10 mg brensocatib, 25 mg brensocatib and all arms combined, respectively. When converted back from log transformation, the median values are 2089, 162, 32 and 200 ng/mL for sputum NE, respectively. Figure S3. Distribution Analysis of Sputum PR3 Activity Collected Over the Trial Duration. PR3 activity in sputum is shown in a quantile-quantile plot of measured values versus predicted standard normal distribution values, in a distribution plot, and in a relative frequency histogram plot. The bar in panel B indicates the mean PR3 activity for each arm. Median activity values are 3.63, 3.60, 3.46, and 3.55 log (ng/mL) for sputum PR3 for placebo, 10 mg brensocatib, 25 mg brensocatib and all arms combined, respectively. When converted back from log transformation, the median values are 4266, 3981, 2884 and 3548 ng/mL for sputum PR3, respectively. Figure S4. Distribution Analysis of Sputum CatG Activity Collected Over the Trial Duration. CatG activity in sputum is shown in a quantile-quantile plot of measured values versus predicted standard normal distribution values, in a distribution plot, and in a relative frequency histogram plot. The bar in panel B indicates the mean CatG activity for each arm. Median activity values are 1.29, 0.29, 0.29 and 0.29 log (ng/mL) for sputum PR3 for placebo, 10 mg brensocatib, 25 mg brensocatib and all arms combined, respectively. When converted back from log transformation, the median values are 19, 1.9, 1.9 and 1.9 ng/mL for sputum PR3, respectively.

The loss of smell related to SARS-CoV-2 infection is one of the most prevalent symptoms of COVID-19. It is now clear that this symptom is related to the massive infection by SARS-CoV-2 of the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamster, we show here that while apoptosis remains at a low level in damaged infected epithelium, the latter is invaded by innate immunity cells. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we reduced the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease of SARS-CoV-2 infection levels in the nasal cavity. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus.