Outer Membrane Proteins of Pathogenic Oral Treponemes Inhibit Actin Rearrangement and Antimicrobial Functions of Neutrophils

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Periodontal disease is a bacterially induced inflammatory condition affecting 47% of adults in the United States and is the number one cause of tooth loss worldwide. This condition is characterized by the destruction of tooth-supporting structures resulting from dysbiosis between the host immune system and the normally commensal oral biofilm. Treponema denticola, Treponema maltophilium, and Treponema lecithinolyticum are three understudied bacterial species abundant in the polymicrobial biofilm associated with severe periodontal disease, and a complete understanding of their pathogenic properties is lacking. T. denticola, the most-well- studied oral spirochete, has a prominent virulence factor: the major outer sheath protein (Msp) that dysregulates the functions of host cells, including neutrophils. T. maltophilium and T. lecithinolyticum have Msp-like outer membrane proteins called MspA and MspTL, respectively. Neutrophils are key innate immune cells that protect oral tissues from pathogenic bacteria by coordinating cellular signaling, structural elements, and cell function. Msp inhibits neutrophil function by disrupting the balance of phosphoinositides, cellular lipid metabolites key for intracellular signaling. This disruption involves altered regulation of the PI3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) axis, leading to inappropriate remodeling of the actin cytoskeleton, impaired chemotaxis, and altered functioning of neutrophils. A remaining gap in our knowledge is how these understudied Treponema proteins modulate actin dynamics to impair other crucial neutrophil properties. The overall objective of this project is to characterize how these Treponema species and their surface proteins manipulate neutrophil cytoskeleton signaling pathways and granule release to promote survival. We hypothesize that Msp-like proteins dysregulate actin remodeling in neutrophils to promote bacterial survival. To test this hypothesis, this project aims to (1) characterize the effects of Msp proteins on the PI3K/PTEN axis and actin branching dynamics and (2) assess the ability of Treponema species and their Msp proteins to promote survival by modulating neutrophil recruitment and degranulation. To achieve these aims, I will utilize a variety of methods, including analyses of actin incorporation, immunological techniques, microscopy, flow cytometry, animal models, molecular biology, and microbiological techniques. Completion of this project will provide valuable insight into the interactions between spirochetes and the immune system and how these relationships drive disease progression. The mentoring and training plan to be performed within the multidisciplinary research environment at the University at Buffalo will provide me with the scientific and professional development skills necessary to successfully transition to the next stage of a successful research career.