Emerging role of oral spirochetes to promote neuroinflammation and dysfunction

Periodontitis is a common chronic inflammatory condition of the tooth-supporting tissue, affecting up 50% of the population and two-thirds of the elderly in the United States. Progressive neurological deterioration during poses a significant burden for the elderly population, with high prevalence of cognitive decline in those over the age of

85-years old. Emerging evidence suggests a link between poor oral health, cognitive impairment and neurological conditions. The blood-brain barrier (BBB) and associated cellular milieu of the neurovascular unit (NVU) including microglia, pericytes and astrocytes serve as a crucial interface for neuroimmune communication and

physiological maintenance of the central nervous system. Healthy aging is associated with normal physiological changes in the integrity and function of both the BBB and NVU. Sustained dysbiotic chronic systemic inflammation of periodontitis may contribute to prolonged neuroinflammation, functional cognitive impairment

and neurodegenerative dysfunction. Dysbiosis of the dental plaque microbiome community occurs during periodontitis, with increased abundance of multiple species of Treponema spirochetes. Continued evidence indicates positive correlation of Treponema species in dental plaque and their presence in brain and neurological

tissue of patients with cognitive disorders. Despite known extraoral relationships of these understudied spirochete organisms, there is still a significant gap in knowledge of how oral bacteria mechanistically impact the BBB and NVU to contribute to cognitive disorders. Our central hypothesis is that periodontal pathogens including

Treponema species promote glial activation with BBB dysfunction, and thus contributes to a significant neuroinflammatory response and consequent neurodegeneration; playing a key pathophysiological role in bacterial-induced modulation of the neuro-immune axis. We will test our hypothesis by completion of the

following specific aims: 1. Characterize the ability of oral spirochetes to promote blood-brain barrier (BBB) dysfunction and 2. Assess the ability of oral spirochetes to drive an inflammasome-mediated neuroinflammatory phenotype and transcriptional signature in glial cells of neurovascular unit. Understanding the underlying

mechanisms involved in the interaction between microbes, inflammation and cellular components of the nervous system is vital for the early intervention and improvement of neurological disorders.