An antioxidant enzyme to suppress hyperinflammation induced by SARS-CoV-2

项目摘要 COVID-19大流行给全球人民造成了重大损失，目前的治疗主要是 支持虽然COVID-19的发病机制仍然难以捉摸，但越来越多的证据表明， 严重COVID-19患者亚组可能存在病毒驱动的过度炎症和免疫反应， 失调我们在此提出活性氧有助于炎症过度和免疫反应。 严重的COVID-19患者中的失调，可以通过抗氧化酶-过氧化氢酶治疗， 调节细胞因子的产生，保护免受氧化损伤，并抑制SARS-CoV-2的复制。这 基于过氧化氢酶的治疗，过氧化氢酶是肝脏中普遍存在的最丰富的抗氧化酶， 红细胞和肺泡上皮细胞是分解过氧化氢的最有效催化剂， 最小化下游活性氧物质。过氧化氢酶作为治疗剂的潜力已经被证实。 在体外和小鼠模型中探索了不同的疾病，包括流感相关肺炎， 由呼吸道合胞病毒（RSV）引起的呼吸道感染，以及与 氧化应激然而，过氧化氢酶的功效受到其稳定性差和血浆短的阻碍 半衰期特别是，在COVID-19患者的背景下，肺泡细胞的死亡和炎症可能会导致 导致蛋白酶的高局部浓度，进一步恶化了过氧化氢酶的稳定性。我们最近 发表了使用纳米胶囊技术的过氧化氢酶的有效递送系统。过氧化氢酶由 纳米帽有助于调节细胞因子的产生并保护氧化损伤，如在 人白细胞和肺泡上皮细胞，并抑制SARS-CoV-2在恒河猴中的复制， 没有明显的毒性。在这个建议中，我们将进一步研究过氧化氢酶的免疫调节作用 纳米胶囊对SARS-CoV-2离体诱导的过度炎症的作用，进一步优化了它们的生物分布， 药代动力学和对SARS-CoV-2感染器官的递送效率，并测试它们在 SARS-CoV-2感染小鼠出现类似严重COVID-19的呼吸道疾病。成功的这项 该项目可能为大流行病提供有效的治疗解决方案， 一般由病毒感染引起的炎症过度。

PROJECT SUMMARY The COVID-19 pandemic has taken a significant toll on people worldwide, and current treatment is mainly supportive. While the pathogenesis of COVID-19 remains elusive, accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have virally driven hyperinflammation and immune dysregulation. We propose herein reactive oxygen species contribute to hyperinflammation and immune dysregulation in severe COVID-19 patients, which can be treated by an antioxidant enzyme—catalase that regulates cytokine production, protects against oxidative injury, and represses replication of SARS-CoV-2. This therapeutic based on catalase, the most abundant antioxidant enzyme ubiquitously present in the liver, erythrocytes and alveolar epithelial cells, is the most effective catalyst to breakdown hydrogen peroxide and minimize the downstream reactive oxygen species. The potential of catalase as a therapeutic agent has been explored for different diseases in vitro and in mouse models, including influenza-associated pneumonia, respiratory infections caused by respiratory syncytial virus (RSV), and inflammatory disease associated with oxidative stress. However, the efficacy of catalase has been hampered by its poor stability and short plasma half-life. Particularly, in the context of COVID-19 patients, death of the alveolar cells and inflammation could result in high local concentrations of proteases, further deteriorating the stability of catalase. We recently published an effective delivery system of catalase using the nanocapsule technology. Catalase delivered by nanocapsules assists to regulate production of cytokines and protect oxidative injury, as demonstrated in human leukocytes and alveolar epithelial cells, and repress replication of SARS-CoV-2 in rhesus macaques, without noticeable toxicity. In this proposal, we will further investigate the immunoregulatory effect of catalase nanocapsules on hyperinflammation induced by SARS-CoV-2 ex vivo, further optimize their biodistribution, pharmacokinetics, and delivery efficiency to SARS-CoV-2 infected organs, and test their therapeutic efficacy in the SARS-CoV-2 infection mice developing respiratory disease resembling severe COVID-19. Success of this project may provide an effective therapeutic solution for the pandemic, as well as treatment of hyperinflammation induced by virus infection in general.