Local tolerance and efficient innate immune activation of primary human respiratory cells by the recombinant flagellin FLAMOD

ABSTRACT: Antibiotic-resistant respiratory infections can lead to treatment failure, highlighting the need for alternative strategies. FLAMOD, a recombinant flagellin and Toll-like receptor 5 agonist, stimulates innate immunity when delivered intranasally. In mouse models, FLAMOD is effective against bacterial pneumonia. The protective efficacy was associated with activation of airway epithelial cells. This study aimed to assess the tolerance of human primary respiratory epithelium to FLAMOD administered apically as liquid droplets or by nebulization, to measure the FLAMOD-mediated innate immune response, and to analyze the pharmacokinetics of FLAMOD. We used epithelia reconstituted from human nasal and bronchial (MucilAir™), small airways (SmallAir™) and alveolar (AlveolAir™) primary epithelial cells, cultured at the air-liquid interface. We report that daily administration of escalating doses of FLAMOD for 5 days was well tolerated in the various epithelium as epithelial integrity, cilia motion and viability were not affected. FLAMOD was rapidly degraded and leakage into the basal compartment was not detected. An immunomodulatory effect was identified in each epithelium, and found to be FLAMOD dose-dependent with an effective dose in the picomolar range. Similar safety profile and immune responses were obtained with airway epithelium from cystic fibrosis and chronic obstructive pulmonary disease patients. In conclusion, this study supports the development of the use of TLR5 agonist for respiratory delivery to stimulate innate defenses against infections of vulnerable patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313945 | GEO | 2026/08/24

REPOSITORIES: GEO