Pentosan polysulfate sodium limits pulmonary inflammation in a SARS-CoV-2 mouse model

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains prevalent globally, causing severe pulmonary inflammation and mortality in up to 10% of patients. While the introduction of effective vaccines has substantially reduced the number of severe coronavirus disease 2019 (COVID-19) cases, there are currently few available therapeutics that have been developed. Pentosan polysulfate sodium (PPS) has been shown to possess potent anti-inflammatory activity in influenza infection and allergen-induced rhinitis models and was recently demonstrated to inhibit SARS-CoV-2 infection in vitro . As such, we hypothesized that PPS may represent an attractive therapeutic that could be utilized for SARS-CoV-2 infection and COVID-19. Using the K18-hACE2 mouse model of SARS-CoV-2 infection, we administered PPS (6 mg/kg) from either 1 (early) or 3 (late) days post-infection via intranasal instillation and then examined the efficacy in mitigating viral-induced inflammation and severe disease outcomes. We found that the early administration of PPS was accompanied by significant improvements in weight loss, clinical disease presentation, and neutrophilic airway inflammation. Early PPS administration also significantly reduced pro-inflammatory cytokine production at both the mRNA and protein levels while having no impact on viral titers or interferon and antiviral gene expression. Histologically, early treatment significantly prevented severe pulmonary inflammation and tissue remodeling. Comparatively, late administration of PPS worsened weight loss and clinical disease presentation following SARS-CoV-2 infection. Moreover, late administration was unable to prevent significant increases in pro-inflammatory cytokines and was further associated with significantly downregulated antiviral-associated genes. Histological examination also showed no protection in the late PPS administered groups. Taken together, these findings underscore the significance of time-dependent administration and demonstrate the therapeutic potential of PPS for treatment of SARS-CoV-2-induced inflammation. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause infections globally, with most cases resulting in mild to moderate disease outcomes. However, approximately 10% of patients experience virally induced hyperinflammation leading to poor outcomes. As such, new or repurposed therapeutics need to be rapidly implemented to address this urgent medical need. Here, we show that pentosan polysulfate sodium (PPS) is a leading Food and Drug Administration (FDA)-approved therapeutic that significantly mitigates SARS-CoV-2-induced pulmonary inflammation. Critically, timing of PPS during the infection establishment and progression is critical for PPS efficacy, highlighting time-dependent responses that must be considered for further human clinical implementation. The findings from this study demonstrate that PPS holds significant promise as a repurposed anti-inflammatory agent for SARS-CoV-2 infection.