Fellowship for Dayron M. Leyva Rodriguez: Spirochete Neutrophil Interactions Initiate Vascular Inflammation Promoting Aortic Endothelial Dysfunction

Project Summary/Abstract Periodontitis is a chronic inflammatory condition affecting about 47% of the population in the United States, and is a potential risk factor for systemic co-morbidities as individuals with poor oral hygiene are 30% more likely to develop adverse cardiovascular events. Periodontitis is characterized by a dysbiotic subgingival microbial community, with a high abundance of spirochetes, including Treponema denticola, together with local gingival inflammation allowing for transmigration of bacterial products and inflammatory mediators to the circulation. Inflammation-driven endothelial cell dysfunction leading to vascular permeability is a critical factor in initial cardiovascular disease (CVD) pathogenesis. Emerging evidence has implicated neutrophil infiltration in the early stages of endothelial cell dysfunction and progression of CVD. T. denticola has been detected in human atheromas, along with active propagation to the aortic tissue with neutrophil-rich immune cell recruitment in murine models of oral T. denticola infection. T. denticola and T. denticola-produced outer-membrane vesicles (OMVs) dysregulate neutrophil function along with promoting distinct neutrophil cytokine profiles characterized by the secretion of the understudied IL-6 family cytokine, Oncostatin M (OSM). OSM is elevated locally in the periodontal pocket and systemically during periodontitis. Furthermore, OSM has also been implicated in cardiovascular pathologies and may support endothelial changes in atheroprone environments. Effective cellular junctions and functional signaling are required to maintain vascular endothelial integrity and disruption of these molecular complexes together with cellular activation are early hallmarks of endothelial dysfunction leading to atheroma development. A gap in knowledge remains in the mechanistic understanding of how neutrophil cytokine signaling and spirochete interactions orchestrate initial endothelial changes to promote vascular pathology. The overall objective of this project is to characterize oral bacteria and inflammatory cytokine signaling processes which promote aortic endothelial cell dysfunction. It is hypothesized that T. denticola- mediated interactions and neutrophil-derived OSM signaling support endothelial junctional integrity and inflammatory signaling pathways to promote a pro-atheroma vascular environment. Two aims will be pursued to test this hypothesis: 1) identify molecular mechanisms of endothelial dysfunction during exogenous OSM priming and 2) investigate the molecular regulation of endothelium activation by T. denticola exposure. To achieve these aims, a variety of methods will be used; including immunological assays, dynamic in vitro models, microscopy, flow cytometry, animal models, and microbiological techniques. Completion of this project will provide valuable insight into the interactions of spirochetes, inflammatory cytokine signaling, and neutrophils to promote endothelial cell dysfunction. The mentoring and proposed training plan will be performed within a multidisciplinary research environment at the University at Buffalo, which will provide the trainee with both the scientific and professional development skills necessary to transition to the next stage of a successful research career.