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 P. gingivalis; however, P. gingivalis can also inhabit the oral cavity in the absence of disease. The interaction between P. gingivalis and gingival epithelial cells 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 define the outcomes of the interaction between P. gingivalis and gingival epithelial cells as they relate colonization of the organism and the generation of immune dysbiosis. We shall also continue our major focus on the role of the functionally versatile SerB invasin and modulin of P. gingivalis. Cofilin, an actin depolymerizing protein, is required for P. gingivalis invasion. We will examine the ability of SerB to dephosphorylate and inactivate LIMK kinase which will lead to activation of cofilin. We will then investigate the impact of P. gingivalis on ROCK, PAK1 and MK2 pathways that lead to activation of LIMK. These interactions will be observed within the cell by live cell imaging. P..gingivalis can suppress IL-8 production in part through regulation of actin dynamics. We shall study the cofilin dependent, actin mediated suppression of IL-8 by P. gingivalis. The immune disruptive ability of P. gingivalis also extends to T-cell chemokines, and the mechanism of suppression of IP-10, ITAC and Mig will be studied. We will also begin to assess biological relevance by examining T-cell migration in response to epithelial cells infected with P. gingivalis. These studies will provide a detailed molecular analysis of the targeting of host signal transduction by P. gingivalis along with the role of a specific effector phosphatase. 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 #
5R37DE011111-22
Application #
8788827
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lunsford, Dwayne
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
22
Fiscal Year
2015
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40202
Edmisson, Jacob S; Tian, Shifu; Armstrong, Cortney L et al. (2018) Filifactor alocis modulates human neutrophil antimicrobial functional responses. Cell Microbiol 20:e12829
Lee, Jae Y; Miller, Daniel P; Wu, Leng et al. (2018) Maturation of the Mfa1 Fimbriae in the Oral Pathogen Porphyromonas gingivalis. Front Cell Infect Microbiol 8:137
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:
Inaba, Hiroaki; Amano, Atsuo; Lamont, Richard J et al. (2018) Cell Cycle Arrest and Apoptosis Induced by Porphyromonas gingivalis Require Jun N-Terminal Protein Kinase- and p53-Mediated p38 Activation in Human Trophoblasts. Infect Immun 86:
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
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
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
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

Showing the most recent 10 out of 55 publications