Tissue-specific role of ADAM proteases in infectious lung diseases

• Applicant: Professorin Dr. Daniela Yildiz
• Subject Area: Pharmacology ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Pneumology, Thoracic Surgery
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274881547

The lung is normally protected against bacterial infections by the epithelium and the resident alveolar macrophages as first line of defense. If these barriers are overridden, an inflammatory response is initiated leading either to resolution of the infection or to persisting damage of the lung. This sequence of leukocyte recruitment, permeability changes, tissue damage, and initiation of repair is regulated by the interplay of soluble and surface expressed mediators originating from endothelial cells, smooth muscle cells, epithelial cells, and leukocytes. Many of these molecules including cytokines, chemokines, cytokine receptors, adhesion molecules, growth factors, scavenger and pattern recognition receptors, and surface proteoglycans exist as transmembrane molecules and are released by ectodomain shedding through the a disintegrin and metalloproteinases (ADAM) 10 and 17. Our previous work shows that lung ADAM10 and 17 contribute to the acute inflammatory response in a cell-type specific manner. They function in the regulation of endothelial permeability, proinflammatory mediator secretion by smooth muscle cells, and the migratory response of leukocytes. Yet, the contribution of ADAMs towards antibacterial defense in the lung remains largely unexplored.Our first data indicate that ADAM10 and ADAM17 are differentially involved in the clearance of bacteria by leukocytes and the apoptosis of endothelial and epithelial cells. Expression of ADAM10 and 17 mRNA was found to be differentially regulated after BCG infection, and increased levels of shed substrates (CXCL16 and JAM-A) were detected in the bronchoalveolar lavage (BAL) fluid of S. pneumoniae-infected animals. Our hypothesis is that ADAM proteases critically contribute to the development of bacteria-induced pneumonia in a lung cell-specific manner by the regulation of particle entrance, lung cell activation, lung cell damage, and bacterial clearance. This will be analyzed in detail using tissue-specific knockout mice in a model of infection with Gram-positive (S. pneumoniae) and Gram-negative (P. aeruginosae) bacteria, respectively, and the investigation of the underlying mechanisms in cultured lung cells and leukocytes. Our intention is to evaluate the potential and the side effects of ADAM10 and 17 as antiinflammatory drug targets in infectious lung diseases.

• DFG Programme: Research Grants