Barrier dysfunction in nasal epithelium contributes to persistent inflammation in long COVID

Background: Long COVID (LC) is characterized by persistent symptoms associated with chronic inflammation and immune dysregulation, but the local tissue mechanisms driving these processes remain poorly understood. Objective: Given that the nasal epithelium is the primary entry and infection site for SARS-CoV-2, we aimed to investigate its role in LC and its potential contribution to systemic immune activation. Methods: We analyzed nasal epithelial samples and peripheral blood from participants in the Precision Medicine for More Oxygen (P4O2) COVID-19 cohort, post–COVID-19 individuals, and healthy controls. We assessed epithelial barrier integrity, evaluated wound healing, and explored cytokine profiles. Transcriptomic analysis was performed via RNA sequencing. Blood innate lymphoid cells (ILCs) were phenotyped by flow cytometry and stimulated in vitro for functional assays. Results: Among a subgroup of LC patients, nasal epithelial cells showed impaired barrier function, reduced expression of ZO-1 and occludin and exaggerated sensitivity to viral triggers. Despite faster wound closure, the epithelial repair was reduced. The LC nasal epithelium exhibited increased cytokine production, including IL-1β and transcriptomic signatures of inflammation, including upregulation of interferon pathways. Furthermore, we found that TFs ATF3 and EGR1 were downregulated in LC. Elevated IL-1β levels in nasal epithelium promoted ILC activation and plasticity toward IFN-γ–producing ILCs in blood. Conclusion: While multiple organ systems are implicated in LC, our findings identified nasal epithelial dysfunction in a subgroup of LC patients and chronic activation as potential contributors to systemic immune dysregulation. The IL-1β–IFN-γ axis represents a novel targetable pathway that may support precision therapies for LC.