Müller Talitha, Dzanibe Sonwabile, Day Cascia, Mpangase Phelelani Thokozani, Chimbetete Tafadzwa, Pedretti Sarah, Schwager Sylva, Gray Clive M, Sturrock Edward, Peter Jonny
Division of Allergology and Clinical Immunology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Sci Rep. 2025 Apr 14;15(1):12799. doi: 10.1038/s41598-025-96161-w.
Renin-angiotensin system (RAS) dysregulation is an important component of the complex pathophysiology of SARS-CoV-2 and other coronavirus infections. Thus, angiotensin-converting enzyme 2 (ACE2), the entry receptor and key to the alternative RAS, was proposed as a severity/prognostic biomarker for risk-stratification. However, experimental RAS data from diverse cohorts are limited, particularly analyses integrating RAS with immune biomarkers. Participants (n = 172) in Cape Town were sampled longitudinally (including a recovery timepoint [> 3-month]), across WHO asymptomatic to critical severity. Using fluorometric assays and LC-MS/MS RAS Fingerprinting, results show serum ACE1 activity significantly decreases with increasing COVID-19 severity (P < 0.01) and mortality (P < 0.05), while increased ACE2 activity is associated with worse severity (P < 0.01). Neither enzyme activity correlates with viral load proxy or nasal ACE mRNA levels. ACE1 and ACE2 activities were the most effective severity biomarkers compared to 96 established immune markers obtained via proximity extension assay, as demonstrated by principal component analysis. A multivariate variable selection model using random forest classification identified biomarkers discriminating COVID-19 severity (AUC = 0.82), the strongest being HGF, EN-RAGE, cathepsin L. Adding ACE1 activity and anti-SARS-CoV-2 antibody titres improved differentiation between ambulatory and hospitalised participants. Notably, RAS dysregulation has unique severity associations in coronavirus infections with implications for treatment and pathophysiological mechanisms.
肾素-血管紧张素系统（RAS）失调是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和其他冠状病毒感染复杂病理生理学的重要组成部分。因此，血管紧张素转换酶2（ACE2）作为替代RAS的进入受体和关键因素，被提议作为风险分层的严重程度/预后生物标志物。然而，来自不同队列的实验性RAS数据有限，尤其是将RAS与免疫生物标志物整合的分析。开普敦的172名参与者进行了纵向采样（包括恢复时间点[>3个月]），涵盖了世界卫生组织定义的从无症状到危重症的所有严重程度。使用荧光测定法和液相色谱-串联质谱（LC-MS/MS）RAS指纹图谱分析，结果显示，随着COVID-19严重程度的增加（P<0.01）和死亡率的上升（P<0.05），血清ACE1活性显著降低，而ACE2活性增加与更严重的病情相关（P<0.01）。两种酶的活性均与病毒载量替代指标或鼻腔ACE mRNA水平无关。与通过邻近延伸分析获得的96种既定免疫标志物相比，ACE1和ACE2活性是最有效的严重程度生物标志物，主成分分析证明了这一点。使用随机森林分类的多变量选择模型确定了区分COVID-19严重程度的生物标志物（曲线下面积[AUC]=0.82），其中最强的是肝细胞生长因子（HGF）、淀粉样前体蛋白羧基末端片段（EN-RAGE）、组织蛋白酶L。加入ACE1活性和抗SARS-CoV-2抗体滴度可改善门诊和住院参与者之间的区分。值得注意的是，RAS失调在冠状病毒感染中具有独特的严重程度关联，对治疗和病理生理机制具有重要意义。
