Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. One of the predominant pathogens in periodontal disease is the gram- negative anaerobe P. gingivalis. However, P. gingivalis can also inhabit the oral cavity in the absence of overt disease and can participate in a balanced interaction with host cells. Epithelial cells that line the gingival crevice function both as a physical barrier and as sensors of microbial colonization. The outcome of the interaction between P. gingivalis and gingival epithelial cells, therefore, makes a significant contribution to the degree of equilibrium between host and microbe, and to overall gingival health status. P. gingivalis can manipulate epithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram host innate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase, SerB. The goal of this proposal is to define the mechanism of action of SerB as it relates to uptake of the organism by gingival epithelial cells and modulation of innate immunity. Firstly, the ability of SerB to dephosphorylate and activate cofilin will be examined. Cofilin regulates actin dynamics through mediating the disassembly of actin filaments, and our hypothesis is that activation of cofilin by SerB is required for P. gingivalis entry. This will be tested through up and down regulation of cofilin activity by siRNA and transfections with activation-altered cofilin. Secondly, we shall determine the signaling pathways modulated by SerB that converge on suppression of the chemokine IL-8. The participation of MEK and NF-?B will be investigated by blotting, mobility shift assays and dominant positive and negative mutations. Finally, we shall characterize the interconnectivity between SerB-induced cytoskeletal signaling and IL-8 suppression, by manipulation of actin filament structure and MEK activation status. These studies will provide a detailed molecular analysis of the targeting of host signal transduction by a specific effector phosphatase of P. gingivalis. Ultimately, the knowledge gained could be developed into strategies that could be utilized to intervene in the P. gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.

Public Health Relevance

P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we will examine the interactions between P. gingivalis and the human cells that are colonized by the organism. The information to be gathered could be used to identify targets for novel therapeutic agents designed to interfere with the colonization and survival strategies of P. gingivalis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DE011111-17
Application #
7783834
Study Section
Special Emphasis Panel (ZRG1-MOSS-B (02))
Program Officer
Lunsford, Dwayne
Project Start
1995-04-01
Project End
2010-11-30
Budget Start
2010-01-01
Budget End
2010-11-30
Support Year
17
Fiscal Year
2010
Total Cost
$344,458
Indirect Cost
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
Jimenez Flores, E; Tian, S; Sizova, M et al. (2017) Peptoanaerobacter stomatis Primes Human Neutrophils and Induces Granule Exocytosis. Infect Immun 85:
Glowczyk, Izabela; Wong, Alicia; Potempa, Barbara et al. (2017) Inactive Gingipains from P. gingivalis Selectively Skews T Cells toward a Th17 Phenotype in an IL-6 Dependent Manner. Front Cell Infect Microbiol 7:140
Hajishengallis, George; Lamont, Richard J (2016) Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts. Trends Microbiol 24:477-89
Hutcherson, J A; Gogeneni, H; Yoder-Himes, D et al. (2016) Comparison of inherently essential genes of Porphyromonas gingivalis identified in two transposon-sequencing libraries. Mol Oral Microbiol 31:354-64
Gao, Shegan; Li, Shuoguo; Ma, Zhikun et al. (2016) Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect Agent Cancer 11:3
Gu, Zhen; Lamont, Gwyneth J; Lamont, Richard J et al. (2016) Resolvin D1, resolvin D2 and maresin 1 activate the GSK3? anti-inflammatory axis in TLR4-engaged human monocytes. Innate Immun 22:186-95
Sztukowska, Maryta N; Ojo, Akintunde; Ahmed, Saira et al. (2016) Porphyromonas gingivalis initiates a mesenchymal-like transition through ZEB1 in gingival epithelial cells. Cell Microbiol 18:844-58
Armstrong, Cortney L; Miralda, Irina; Neff, Adam C et al. (2016) Filifactor alocis Promotes Neutrophil Degranulation and Chemotactic Activity. Infect Immun 84:3423-3433

Showing the most recent 10 out of 52 publications