Introduction:
Long COVID is described as the persistence of symptoms following acute COVID-19 for >12 weeks and occurs in about 30% of all cases. Nasal epithelium is a primary target for SARS-CoV-2 and involved in the early phase immune response.

Aims:
To assess the role of nasal epithelium and a local tissue micro-environment in long COVID.

Methods:
Phenotype and function of nasal epithelium and innate lymphoid cells(ILC) were analyzed from long COVID patients and healthy controls(HC) using quantitative polymerase chain reaction, transepithelial resistance, scratch assays and flow cytometry. Long COVID samples were collected from Precision Medicine for more Oxygen (P4O2)? COVID-19 participants at 3-6 months post-COVID. Nasal epithelium was cultured at air-liquid-interface and exposed to viral mimic poly(I:C).

Results:
An activated inflammatory state of nasal epithelium in long COVID (n=10) compared to HC(n=5) was found. In nasal epithelium, the relative gene expression of pro-inflammatory cytokines, including interleukin (IL)6, IL8, CXCL10, CCL5, TNFA and IL1B, was increased at baseline and after 24-hour exposure to poly(I:C). Furthermore, increased frequencies of IFN-gamma producing ILCs were found in the blood of long COVID patients, that in vitro produced more IFN-gamma after exposure to epithelium-derived IL-1beta compared to HC. Ex vivo, this inflammatory state resulted in a reduced barrier function and increased regeneration potential of long COVID nasal epithelium.

Conclusions:
In Long COVID, epithelium-derived IL-1beta is potentially a key mediator in shaping the inflammatory airway tissue micro-environment by inducing IFN-gamma production in immune cells and consequently disturbing the epithelial barrier function.