Pneumonia induced trained immunity as a driver of pathogenic inflammation within the lung

Description du projet

Comment la pneumonie bactérienne induit une immunité entraînée

L’inflammation joue un rôle clé dans les affections respiratoires, où des infections antérieures peuvent déclencher des changements dans les macrophages. Les infections grippales répétées endommagent les poumons, tandis que la pneumonie bactérienne augmente la production de monocytes, exacerbant ainsi l’inflammation. Soutenu par le programme Actions Marie Skłodowska-Curie, le projet Trained_Lung étudiera comment la pneumonie bactérienne induit une immunité entraînée, provoquant une inflammation excessive et des lésions pulmonaires en cas d’exposition à d’autres bactéries ou à des polluants environnementaux. Le projet identifiera les agents pathogènes qui entraînent les macrophages humains, étudiera les réponses inflammatoires secondaires à différentes bactéries, examinera la myélopoïèse de la moelle osseuse et la fonction des macrophages après une pneumonie chez la souris, évaluera comment ces changements affectent la fonction pulmonaire, et analysera l’impact des macrophages entraînés sur les réponses immunitaires dans les organoïdes pulmonaires humains dérivés de CSPi.

Objectif

The world health organisation has labeled inflammatory diseases the greatest threat to human health. Inflammation is a major cause of pathogenesis in respiratory conditions such as bronchiectasis, ARDS, and COPD. There is a growing appreciation that our prior pathogen exposure can induce trained immunity in macrophages. Trained_Lung will explore how bacterial pneumonia induces central trained immunity and how this can lead to excessive inflammation and lung damage, in response to other bacteria or environmental pollutants. Recently it has been shown that repeat exposure to influenza can lead to lung damage due to the altered functionality of lung macrophages, leading to excessive inflammation and damage to the structure of the lung. However, it remains unclear if this is the case for bacterial pneumonia and if it can lead to inappropriate inflammatory response upon rechallenge with other bacterial species or environmental pollutants. I propose that bacterial pneumonia will drive enhanced myelopoiesis and enhance circulating monocyte inflammatory responses. Further, these circulating monocytes will replace resident alveolar macrophage populations over time, seeding the lung with these trained monocytes which will become resident alveolar macrophages. Alveolar macrophages are constantly in contact with a range of bacteria, viruses, PAMPs, and pollutants which all have the potential to drive excessive inflammatory responses. Trained_Lung will identify pathogens that can train human macrophages and examine secondary inflammatory responses to a range of bacterial pathogens and environmental pollutants. Further, myelopoietic changes in the bone marrow and functional changes in macrophages post-pneumonia in mice will be explored, and how these changes impact subsequent challenges in terms of lung function and damage. Finally, Trained_Lung will explore how trained macrophages impact immune responses within iPSC-derived human lung organoids, adding a key translational aspect