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NIH grant 1R01DE035850-01: An experimental platform to investigate the role of polymicrobial synergy in oral inflammatory dysbiosis
Institute: {'code': 'DE', 'abbreviation': 'NIDCR', 'name': 'National Institute of Dental and Craniofacial Research', 'admin_org_id': '12500070', 'admin_funding_url': ''}. PI: Justin Merritt. Award: $557951.
Start: 2026-08-26T00:00:00.
PROJECT SUMMARY
Human inflammatory dysbiotic diseases exhibit a characteristic dysregulation of host inflammatory control
mechanisms in response to the local microbial ecology at disease sites. Paradoxically, it is the host immune
response to these “inflammophilic” communities that is responsible for sustaining their persistence as well as
triggering most of the host tissue destruction. While there is a wealth of evidence in support of the role of
polymicrobial synergism in inflammatory dysbiosis, our mechanistic understanding of the process remains
extremely vague. Even less is understood about the specific host responses responsible for the chronic,
unresolving nature of many oral and extraoral dysbiotic diseases. These fundamental knowledge gaps can be
largely attributed to a conspicuous lack of animal model platforms capable of recapitulating this complex interplay
between microbiome ecology and dysregulated host inflammatory control. In the current proposal, we provide
multiple lines of evidence demonstrating the feasibility of investigating this complex phenotype with a
polymicrobial abscess model system. Using patient-matched clinical specimens of human dental plaque and
odontogenic abscess, we show that injecting mice with human abscess-derived microcosms induces higher
virulence abscesses relative to patient-matched dental plaque-derived microcosms. Furthermore, mouse
passaging experiments demonstrate how inflammatory selective pressure from the mouse immune response
can remodel both dental plaque- and abscess-derived communities into extremely similar reduced diversity
inflammophilic communities that trigger persistent unresolving abscesses. Intriguingly, immunoprofiling
comparison studies of resolving vs. unresolving abscesses revealed a unique neutrophil phenotype and distinct
cytokine response that is only observed in the unresolving abscesses. The proposed studies will employ this
experimental platform to address important mysteries about the connections between polymicrobial synergism
and host inflammatory dysregulation. These studies will also inform the development of a defined consortium
community model of inflammatory dysbiosis, which is a critical resource currently lacking in the field. The project
will be completed in three Specific Aims: 1) Characterize the core community that stratifies with abscess
virulence; 2) Profile the immune responses of resolving and unresolving abscesses; and 3) Develop a defined
consortium synergistic pathogenesis animal model.document fetched 2026-09-06 02:47