T-6 Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
MPA-Q: MPA-QUANTUM, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
Sci Rep. 2022 Aug 20;12(1):14210. doi: 10.1038/s41598-022-18244-2.
Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.
人们已经付出了相当大的努力来更好地理解为什么有些人患有严重的 COVID-19，而另一些人则无症状。这导致了重要的临床发现；患有严重 COVID-19 的人通常会持续经历高水平的炎症，病毒载量下降较慢，表现出失调的 I 型干扰素反应，自然杀伤细胞活性较低，中性粒细胞胞外诱捕网水平升高。这些发现与 COVID-19 的发病机制如何相关尚不清楚。我们提出了一个数学模型，通过关注通过分子模式引发炎症的细胞来阐明这个问题：携带病原体相关分子模式（PAMPs）的感染细胞和产生损伤相关分子模式（DAMPs）的受损细胞。前者信号提示存在病原体，而后者则提示缺氧或缺乏营养等危险。分析表明，SARS-CoV-2 感染可导致 DAMPs 表达细胞与炎症之间的自我维持反馈循环，无法快速清除 PAMPs 和 DAMPs 是导致过度炎症的主要原因。该模型解释了临床发现，并揭示了可增加治疗管理后获得理想临床结果可能性的条件。特别是，分析表明抗病毒药物需要在感染早期给药，才能对疾病严重程度产生影响。该模型的简单性及其与临床发现的高度一致性促使其用于制定新的治疗策略。
