Pathogen Synergy and Immune Subversion in Periodontal Disease

(ABSTRACT) Periodontitis is a highly prevalent, chronic inflammatory disease that destroys the tissues supporting the teeth, ultimately leading to tooth loss. Beyond the oral cavity, periodontitis is linked to serious health conditions, such as heart disease, diabetes, inflammatory bowel disease (IBD), and certain cancers. Despite its broad clinical impact, treatment options remain limited, often relying on non-selective approaches that disrupt both pathogenic and beneficial members of the oral microbiota. A major obstacle to improved therapies is our incomplete understanding of how specific microbial interactions drive inflammation and sustain disease. As a tractable model to elucidate these interactions, this project will leverage a clinically relevant, defined microbial dyad, Fusobacterium nucleatum (Fn) and Campylobacter rectus (Cr). These Gram-negative anaerobes consistently co-expand in periodontitis, as well as IBD, oral, and colorectal cancers, yet the interactions underpinning their mutual proliferation remain poorly understood. Our preliminary data reveal that Fn potentiates Cr respiratory metabolism by supplying a key electron donor (formate) and facilitating access to multiple electron acceptors (thiosulfate, tetrathionate, nitrate) generated through microbial metabolism and host inflammation. In parallel, Fn promotes neutrophil recruitment, while Cr resists phagocytic clearance via its surface (S)-layer, reinforcing a cycle of inflammation and bacterial persistence. Our central hypothesis is that Fn supports Cr fitness and virulence through metabolic cross-feeding and subversion of neutrophil responses. Using our defined two- species system, biofilm co-culture, targeted bacterial mutants, and in vivo models, this project will define the cooperative microbial and immune interactions that drive disease. The proposed work will also test strategies to disrupt these interactions using microbiota-sparing interventions that target metabolic vulnerabilities. By dissecting how microbial synergy fuels host-damaging inflammation, this project will advance our understanding of periodontal disease pathogenesis and inform the development of precision-based therapeutic approaches. Project Number: 1R01DE035865-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Apollo Stacy | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $568,759 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MSOS-L (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11342135