Oliva Justine, Ruffin Manon, Calmel Claire, Gibeaud Aurélien, Pizzorno Andrés, Gaudin Clémence, Chardonnet Solenne, de Almeida Bastos Viviane, Rosa-Calatrava Manuel, Soulé Antoine, Emad Amin, Rousseau Simon, Corvol Harriet, Terrier Olivier, Guillot Loïc
CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France.
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France.
iScience. 2025 Feb 12;28(3):111999. doi: 10.1016/j.isci.2025.111999. eCollection 2025 Mar 21.
Pre-existing respiratory diseases may influence coronavirus disease (COVID-19) susceptibility and severity. However, the molecular mechanisms underlying the airway epithelial response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection severity in patients with chronic respiratory diseases remain unelucidated. Using an model of differentiated primary bronchial epithelial cells, we aimed to investigate the molecular mechanisms of SARS-CoV-2 infection in pre-existing cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Our study revealed reduced susceptibility of CF and COPD airway epithelia to SARS-CoV-2, relative to that in healthy controls. Mechanistically, reduced transmembrane serine protease 2 (TMPRSS2) activity potentially contributed to this resistance of CF epithelium. Upregulated complement and inflammatory pathways in CF and COPD epithelia potentially primed the antiviral state prior to infection. Analysis of a COVID-19 patient cohort validated our findings, correlating specific inflammatory markers (IP-10, SERPINA1, and CFB) with COVID-19 severity. This study elucidates SARS-CoV-2 pathogenesis and identifies potential biomarkers for clinical monitoring.
既往存在的呼吸系统疾病可能会影响冠状病毒病（COVID-19）的易感性和严重程度。然而，慢性呼吸系统疾病患者气道上皮对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染严重程度的分子机制仍不清楚。我们使用分化的原代支气管上皮细胞模型，旨在研究既往存在囊性纤维化（CF）和慢性阻塞性肺疾病（COPD）时SARS-CoV-2感染的分子机制。我们的研究表明，相对于健康对照，CF和COPD气道上皮对SARS-CoV-2的易感性降低。从机制上讲，跨膜丝氨酸蛋白酶2（TMPRSS2）活性降低可能导致了CF上皮的这种抗性。CF和COPD上皮中补体和炎症途径的上调可能在感染前就启动了抗病毒状态。对一组COVID-19患者的分析验证了我们的发现，将特定的炎症标志物（IP-10、SERPINA1和CFB）与COVID-19严重程度相关联。这项研究阐明了SARS-CoV-2的发病机制，并确定了用于临床监测的潜在生物标志物。
