The human oral cavity hosts at least 600 microbial species, many of which are uncultivated and whose roles in human health or disease remain unclear. This is especially true in the subgingival crevice where microbial communities interact through complex food webs forming structured metabolic guilds. These communities potentially lead to diseases of the mouth such as periodontitis, which affects approximately one third of the adult population. Recent, open-ended studies utilizing DNA-based methods have shed new light on the complex nature of subgingival microbial community structure. However, without advances in understanding the physiology of potentially key, uncultivated groups, treatment and more importantly, prevention of diseases such as periodontitis will remain difficult. To address this, we propose a hypothesis driven, targeted approach to selectively bring heretofore uncultivated, disease-associated microorganisms (e. g. candidate phyla TM7 and SR1) into study through advanced cell isolation and high-throughput cultivation techniques. We will employ a proven, immunological-based method, which has successfully been shown to capture rare and uncultivated microorganism from natural environments. This method leverages genomic information to synthesize surface antigens expressed by selected organisms thus avoiding a random approach to enrichment/cultivation. Novel isolates will be studied individually but more importantly, in combination with other species potentially serving as metabolite facilitators or syntrophs found in the same niche and health/disease state. Highly controllable microenvironments will be established using microfluidic systems that allow biofilm cultivation in conjunction with real-time, advanced imaging techniques. Model living hosts will also be established in Drosophila to simulate complex interactions in a biological system. These platforms will enable microcultivation of novel oral microbiota needed to establish integrated comparative and functional genomic studies, and will advance our understanding of the intimate interactions between microbes inhabiting the subgingival environment and their role in disease.

Public Health Relevance

Periodontitis is a disease that affects the bone and tissues that support the teeth, leading to tooth loss and systemic diseases. It is caused by bacteria, but there are so many species in the mouth, many of them uncultured, that it has been difficult to figure out which ones cause disease and how different microbes interact and lead to heath or disease. The proposed studies will use microbial genomic information and advanced microbiological techniques to culture novel microbes and communities and to learn which bacteria are important so that ways to prevent and treat disease may be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE024463-04
Application #
9314531
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Lunsford, Dwayne
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
UT-Battelle, LLC-Oak Ridge National Lab
Department
Type
DUNS #
099114287
City
Oak Ridge
State
TN
Country
United States
Zip Code
37831
Beall, Clifford J; Campbell, Alisha G; Griffen, Ann L et al. (2018) Genomics of the Uncultivated, Periodontitis-Associated Bacterium Tannerella sp. BU045 (Oral Taxon 808). mSystems 3:
Beall, C J; Mokrzan, E M; Griffen, A L et al. (2018) Cultivation of Peptidiphaga gingivicola from subgingival plaque: The first representative of a novel genus of Actinomycetaceae. Mol Oral Microbiol 33:105-110
Cross, Karissa L; Chirania, Payal; Xiong, Weili et al. (2018) Insights into the Evolution of Host Association through the Isolation and Characterization of a Novel Human Periodontal Pathobiont, Desulfobulbus oralis. MBio 9:
Mukherjee, Chiranjit; Beall, Clifford J; Griffen, Ann L et al. (2018) High-resolution ISR amplicon sequencing reveals personalized oral microbiome. Microbiome 6:153
Bowers, Robert M; Kyrpides, Nikos C; Stepanauskas, Ramunas et al. (2017) Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea. Nat Biotechnol 35:725-731
Zhulin, Igor B (2017) By Staying Together, Two Genes Keep the Motor Running. Structure 25:214-215
Adebali, Ogun; Petukh, Marharyta G; Reznik, Alexander O et al. (2017) Class III Histidine Kinases: a Recently Accessorized Kinase Domain in Putative Modulators of Type IV Pilus-Based Motility. J Bacteriol 199:
Adebali, Ogun; Zhulin, Igor B (2017) Aquerium: A web application for comparative exploration of domain-based protein occurrences on the taxonomically clustered genome tree. Proteins 85:72-77
Shankles, Peter G; Timm, Andrea C; Doktycz, Mitchel J et al. (2015) Fabrication of nanoporous membranes for tuning microbial interactions and biochemical reactions. J Vac Sci Technol B Nanotechnol Microelectron 33:06FM03
Zhulin, Igor B (2015) Databases for Microbiologists. J Bacteriol 197:2458-67

Showing the most recent 10 out of 11 publications