Functional programming of alveolar macrophages and susceptibility to pneumonia – Progr-AM

Pneumonia was the leading cause of communicable diseases and the second cause of disability-adjusted life-years in the world in 2019, even before the COVID-19 pandemic. Pneumonia can be either acquired in the community (community-acquired pneumonia, CAP) or during hospitalization (Hospital-acquired pneumonia, HAP). CAP is classically induced by virulent bacteria (such as Streptococcus pneumoniae) or viruses (Flu), and new pathogenic viruses such as SARS-coV2 (COVID-19) can rapidly diffuse in the population. HAP is the most frequent cause of hospital-acquired infections, with 500,000 episodes of HAP being treated every year in Europe. So far, pneumonia is considered to be caused by lung contamination by exogenous pathogens. Treatments thus aim to reduce the bacterial load but have not eradicated treatment failures, and attributable mortality remains estimated at 10%.
Using mouse models of pneumonia, I have shown that during pneumonia, acute inflammation alters alveolar macrophages (AM) programming and response to bacteria. The newly formed AM are characterized by a high metabolic activity but low ability to phagocyte extracellular bacteria. The development of these ‘paralyzed’ AM depends on the cellular microenvironment alterations established during the inflammation. Further, I reproduced these observations in patients with pneumonia, showing that they were associated with clinical outcomes.
By proposing that outcomes of pneumonia are not only driven by the presence of pathogens in the lungs, but by the resulting dysbiosis between weaken microbiome and altered immunity, I developed a novel concept that has the potential to overthrow the classical theory on the genesis of pneumonia and to revolution the prevention and the treatment of this dramatic condition. According to this novel concept, I hypothesized that treatments normalizing host-pathogen interactions rather than sterilizing airways have the potential to enhance the outcomes of infected patients. A better understanding of the regulation of AM functions, which continuously patrol airways to eliminate pathogens rapidly, is required to develop such approaches of pneumonia
Within this proposal, using mice models and respiratory samples collected in patients before and during pneumonia, I will investigate the roles of the cellular and microbial microenvironment in AM programming and pneumonia outcomes. Firstly, I will deeply characterize in respiratory samples collected in humans the function of AM and their cellular and microbial microenvironment. This knowledge will enable the definition of sub-phenotypes of pneumonia associated with treatment failure. Secondly, I will pre-clinically develop new therapeutical candidates targeting either the host or the sub-dominant bacteria to reduce pneumonia morbidity and mortality.
The knowledge gain will enrich European pipelines for innovative treatment of pneumonia and pave the way to personalized medicine respecting the microbiome for severe respiratory infections. Program-AM participates in developing more effective, non-antibiotic treatments and will offer new therapeutic options for highly resistant bacterial infections and for pathogenic viruses. The modulation of macrophages is likely to be extrapolated to other infectious diseases, and to adapt with the need of pathogen variations.