戊聚糖多硫酸钠在SARS-CoV-2小鼠模型中限制肺部炎症

文献信息

中文摘要

未标注： 严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染在全球范围内仍然流行，可在高达10%的患者中引起严重肺部炎症和死亡。尽管有效疫苗的引入已大幅减少重症2019冠状病毒病（COVID-19）病例数，但目前可用的治疗药物仍然很少。戊聚糖多硫酸钠（PPS）已被证明在流感感染和过敏原诱导的鼻炎模型中具有强效抗炎活性，并且最近被证明可在体外抑制SARS-CoV-2感染。因此，我们假设PPS可能是一种有吸引力的治疗药物，可用于SARS-CoV-2感染和COVID-19。使用SARS-CoV-2感染的K18-hACE2小鼠模型，我们在感染后第1天（早期）或第3天（晚期）通过鼻内滴注给予PPS（6 mg/kg），然后检查其在减轻病毒诱导的炎症和严重疾病结局方面的疗效。我们发现，早期给予PPS伴随体重减轻、临床疾病表现和中性粒细胞性气道炎症的显著改善。早期PPS给药还显著降低了mRNA和蛋白水平的促炎细胞因子产生，同时对病毒滴度或干扰素和抗病毒基因表达没有影响。组织学上，早期治疗显著预防了严重肺部炎症和组织重塑。相比之下，SARS-CoV-2感染后晚期给予PPS会加重体重减轻和临床疾病表现。此外，晚期给药无法阻止促炎细胞因子的显著增加，并且还与抗病毒相关基因的显著下调有关。组织学检查还显示，晚期PPS给药组没有保护作用。综上所述，这些发现强调了时间依赖性给药的重要性，并证明PPS在治疗SARS-CoV-2诱导的炎症方面具有治疗潜力。
重要性： 严重急性呼吸综合征冠状病毒2（SARS-CoV-2）继续在全球范围内引起感染，大多数病例导致轻至中度疾病结局。然而，约10%的患者经历病毒诱导的过度炎症，导致不良结局。因此，需要快速实施新的或重新定位的治疗药物，以满足这一紧迫的医疗需求。在这里，我们表明戊聚糖多硫酸钠（PPS）是一种领先的美国食品药品监督管理局（FDA）批准的治疗药物，可显著减轻SARS-CoV-2诱导的肺部炎症。关键的是，在感染建立和进展过程中PPS的给药时机对PPS疗效至关重要，突出了在进一步人体临床实施中必须考虑的时间依赖性反应。本研究的结果表明，PPS作为一种重新定位的抗炎药物用于SARS-CoV-2感染具有重大前景。

英文摘要

UNLABELLED: 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.