| Autor: |
Martin DR; Department of Biomedical Engineering, Lerner Research Institute., Witten JC; Department of Thoracic and Cardiovascular Surgery, Miller Family Heart and Vascular Institute., Tan CD; Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, and., Rodriguez ER; Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, and., Blackstone EH; Department of Thoracic and Cardiovascular Surgery, Miller Family Heart and Vascular Institute., Pettersson GB; Department of Thoracic and Cardiovascular Surgery, Miller Family Heart and Vascular Institute., Seifert DE; Department of Biomedical Engineering, Lerner Research Institute., Willard BB; Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Apte SS; Department of Biomedical Engineering, Lerner Research Institute. |
| Abstrakt: |
Infective endocarditis is a life-threatening infection of heart valves and adjacent structures characterized by vegetations on valves and other endocardial surfaces, with tissue destruction and risk of embolization. We used high-resolution mass spectrometry to define the proteome of staphylococcal and non-staphylococcal vegetations and Terminal Amine Isotopic Labeling of Substrates (TAILS) to define their proteolytic landscapes. These approaches identified over 2000 human proteins in staphylococcal and non-staphylococcal vegetations. Individual vegetation proteomes demonstrated comparable profiles of quantitatively major constituents that overlapped with serum, platelet, and neutrophil proteomes. Staphylococcal vegetation proteomes resembled one another more than the proteomes of non-staphylococcal vegetations. TAILS demonstrated extensive proteolysis within vegetations, with numerous previously undescribed cleavages. Several proteases and pathogen-specific proteins, including virulence factors, were identified in most vegetations. Proteolytic peptides in fibronectin and complement C3 were identified as potential infective endocarditis biomarkers. Overlap of staphylococcal and non-staphylococcal vegetation proteomes suggests a convergent thrombotic and immune response to endocardial infection by diverse pathogens. However, the differences between staphylococcal and non-staphylococcal vegetations and internal variance within the non-staphylococcal group indicate that additional pathogen- or patient-specific effects exist. Pervasive proteolysis of vegetation components may arise from vegetation-intrinsic proteases and destabilize vegetations, contributing to embolism. |
