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

Descrizione del progetto

Il modo in cui la polmonite batterica induce l’immunità addestrata

L’infiammazione svolge un ruolo fondamentale nelle condizioni respiratorie, dove precedenti infezioni sono in grado di innescare cambiamenti nei macrofagi. Ripetute infezioni influenzali danneggiano i polmoni, mentre la polmonite batterica aumenta la produzione di monociti, aggravando l’infiammazione. Sostenuto dal programma di azioni Marie Skłodowska-Curie, il progetto Trained_Lung studierà il modo in cui la polmonite batterica induce l’immunità addestrata, che comporta un’infiammazione eccessiva e danni polmonari in seguito ad esposizione ad altri batteri o a inquinanti ambientali. Il progetto identificherà gli agenti patogeni che addestrano i macrofagi umani, studierà le risposte infiammatorie secondarie a vari batteri, esplorerà la mielopoiesi del midollo osseo e la funzione dei macrofagi post-polmonite nei topi, valuterà le modalità con cui questi cambiamenti influenzano la funzione polmonare ed esaminerà l’impatto esercitato dai macrofagi addestrati sulle risposte immunitarie negli organoidi polmonari umani derivati da cellule staminali pluripotenti indotte.

Obiettivo

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