The World Health Organization estimates that bacterial respiratory infections are the leading cause of illness and death in children and are involved in 20-to-40% of all hospitalizations. Currently, anti-infectious therapies are composed of direct antimicrobial agents, i.e., antibiotics that are administered by oral or systemic routes. Due to increasing therapeutic failures with antibiotics, there is an urgent need for new strategies to improve the treatment of bacterial infections. As described in the call SC1-BHC-14-2019, a promising avenue to overcome treatment failure is to develop novel therapeutic or preventive approaches by specific factors identified in the host. The FAIR project aims to evaluate an alternative strategy based on the activation of innate immunity to treat bacterial respiratory infections of major importance for Public Health. We previously demonstrated the proof-of-concept that respiratory administration of a recombinant Toll-like receptor 5 (TLR5) agonist, i.e., flagellin protects against bacterial pneumonia in the treatment and preventive measures. To this aim, FAIR will: • develop a unique approach using the airways as a delivery route to achieve a local targeting and rapid action at the site of infection, thereby further improving efficacy and reducing systemic side effects • assess whether recombinant flagellin has any therapeutic effectiveness in animal models of respiratory infections with multi-drug resistant bacteria and identify host factors required for the gain of protection. • characterize the safety, biological activity, and pharmacological properties of nebulized flagellin in rodents, and non-human primates • demonstrate the safety/activity in phase 1 clinical trial, identify biomarkers of efficient immunostimulation in humans, and analyze the economic relevance of this alternative approach for the treatment of bacterial pneumonia. The project brings together academic teams with complementary and multidisciplinary late pre-clinical and clinical expertises as well as private companies with unique capability in respiratory delivery systems and preclinical models for drug development. This consortium is built (i) to guarantee progress beyond the state-of-the-art of novel therapeutics from preclinical to clinical proof-of-concept and (ii) to immediately translate the new findings and devices to the next phase of clinical development to provide a new cure for infectious diseases.