Polymicrobial infections are inherently more complex than mono-species infections, and this complexity has been a significant barrier to both a fuller appreciation of pathogenic mechanisms, and to the development of effective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases, and are among the most common infections of humans. Although certain organisms, such as Porphyromonas gingivalis, are considered key pathogens, it is the polymicrobial community that initiates and drives the disease. In vivo imaging studies have shown that oral microbial communities are highly structured; however, little is known regarding the mechanisms that control spatial orientation within communities or the role of spatial structure in pathogenicity. Our ongoing studies have identified and quantified key spatial parameters in synergistic communities of the periodontal pathogen Aggregatibacter actinomycetemcomitans with S. gordonii. In this proposal, we will characterize the molecular basis and biological relevance of spatial parameters controlling the association of P. gingivalis with its community partners. In the first Aim, we will focus on the interaction between P. gingivalis and S. gordonii, a molecularly well-characterized process resulting in elevated pathogenicity of the dual species communities. We will determine the spatial parameters that define the dual species communities and their impact on pathogenicity. Further, through the use of specific mutants, we will assess the impact of known community virulence factors and communication mechanisms on spatial orientation. In the second Aim, we will use Tn-seq and RNA-seq genomic approaches to holistically assess the fitness determinants and transcriptome patterns which control spatial patterning in P. gingivalis and S. gordonii. We will prioritize potential contributors to metabolic synergy for further study of the relationship between spatial proximity and interspecies communication. In the third aim, we will explore Pg genetic pathways important for fitness during infection with a diverse set of co-infecting bacteria. The application of these focused and comprehensively based approaches will allow us to integrate key spatial parameters with molecular interspecies interactions in the context of community pathogenic potential. Successful completion of this project will provide fundamental information regarding the development and regulation of synergistic pathogenicity displayed by spatially defined polymicrobial communities which could ultimately be translated into therapeutic strategies designed to target the community-based pathogenesis that underlies periodontal disease.

Public Health Relevance

Polymicrobial infections are inherently more complex than mono-species infections, and this complexity has been a substantial barrier to both a thorough understanding of pathogenic mechanisms, and to the development of effective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases, and are among the most common infections of humans. The goal of this research is to define the mechanisms that promote disease in polymicrobial oral infection and develop novel therapeutic strategies to treat these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE023193-07A1
Application #
9838561
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Melillo, Amanda A
Project Start
2013-07-19
Project End
2024-06-30
Budget Start
2019-07-05
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Ho, Meng-Hsuan; Lamont, Richard J; Chazin, Walter J et al. (2018) Characterization and development of SAPP as a specific peptidic inhibitor that targets Porphyromonas gingivalis. Mol Oral Microbiol 33:430-439
Sztukowska, Maryta N; Dutton, Lindsay C; Delaney, Christopher et al. (2018) Community Development between Porphyromonas gingivalis and Candida albicans Mediated by InlJ and Als3. MBio 9:
Lamont, Richard J; Koo, Hyun; Hajishengallis, George (2018) The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol 16:745-759
Miller, D P; Wang, Q; Weinberg, A et al. (2018) Transcriptome analysis of Porphyromonas gingivalis and Acinetobacter baumannii in polymicrobial communities. Mol Oral Microbiol 33:364-377
Garg, Neha; Whiteley, Marvin (2018) The chemical topology of a bacterial swarm. J Biol Chem 293:9553-9554
Whiteley, Marvin; Diggle, Stephen P; Greenberg, E Peter (2017) Progress in and promise of bacterial quorum sensing research. Nature 551:313-320
Ibberson, Carolyn B; Stacy, Apollo; Fleming, Derek et al. (2017) Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nat Microbiol 2:17079
Kuboniwa, Masae; Houser, John R; Hendrickson, Erik L et al. (2017) Metabolic crosstalk regulates Porphyromonas gingivalis colonization and virulence during oral polymicrobial infection. Nat Microbiol 2:1493-1499
Miller, Daniel P; Hutcherson, Justin A; Wang, Yan et al. (2017) Genes Contributing to Porphyromonas gingivalis Fitness in Abscess and Epithelial Cell Colonization Environments. Front Cell Infect Microbiol 7:378
Ho, Meng-Hsuan; Lamont, Richard J; Xie, Hua (2017) A novel peptidic inhibitor derived from Streptococcus cristatus ArcA attenuates virulence potential of Porphyromonas gingivalis. Sci Rep 7:16217

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