The Role of TREM-2 in Pneumonia

Pneumonia, whether it is community-acquired or secondary following influenza infection, is a frequent and major challenge for human health. The pathogenesis of pneumonia is complex and involves both pathogen specific factors and the host immune response. The main contributors to pulmonary immunity during bacterial pneumonia are alveolar macrophages and respiratory epithelial cells. Both cell types express certain recognition receptors that sense the presence of pathogens and elicit an inflammatory response upon encounter of bacteria. The precise regulation of this inflammatory response is the topic of this proposal, as this regulation 1) ultimately determines the outcome during infection, 2) is poorly understood and 3) provides a potential target for therapeutic interventions. In this project, we want to specifically examine the role of an important regulator of inflammation, called triggering receptor expressed on myeloid cells 2 (TREM-2), in pneumonia. Our preliminary data clearly show that TREM-2, which is expressed on both alveolar macrophages and respiratory epithelial cells, exerts cell-type specific functions and that it plays a significant role during pneumococcal pneumonia. Yet, we don`t fully understand the contribution of TREM-2 expression on each cell type to the course of the disease. We want to further delineate this several ways, that encompass mouse models, cell culture and molecular and biochemical approaches. These studies are expected to provide a deeper understanding of how pulmonary innate immunity is shaped by TREM-2 during pneumonia and the effects of this immune receptor on alveolar macrophage and epithelial cell mediated innate immune responses. We believe that these findings will thus have a significant translational impact and could pave the way for future studies such as examining TREM-2 in the context of post- influenza pneumonia.

Streptococcus pneumoniae (S. pneumoniae) is the major causative pathogen of community acquired pneumonia, a significant health problem worldwide. The continuing rise in antibiotic resistance stresses the need for better insights into how the body defends itself against this pathogen. The early innate immune response that constitutes bacterial phagocytosis, complement activation and inflammation is critical for the outcome during pneumonia. The Triggering receptor expressed on Myeloid cells 2 (TREM-2) is a cell surface receptor that has been best studied in the bone and brain and has recently been implicated in Alzheimers disease. But the biological functions of this receptor within other bodily organs including the lung are poorly understood. In this proposal, the findings of which were published in the prestigious open access journal PLOS Pathogens, we examined the function of TREM-2 in pulmonary host defense during pneumococcal pneumonia. We could show that lung macrophages deficient in TREM-2 behave very differently to those in bone and TREM-2 exerts suppressive effects on bacterial phagocytosis in this cell type. This occurs via TREM-2 attenuating levels of complement component C1q, an opsonin that enhances phagocytosis that is crucial for defense against pneumonia. In the context of lung infections, we show that TREM-2 deficient animals clear bacteria better and exhibit improved outcome during pneumococcal pneumonia. These data are the first to describe a role for TREM-2 in clinically important lung infections and importantly link this receptor to pathways that regulate opsonin production.