Periodontitis is a chronic inflammatory disease affecting the tissues that surround and support the teeth. In the United States, approximately 65 million people are affected by this condition. Its occurrence is also associated with many important systemic diseases such as cardiovascular disease,rheumatoid arthritis, and Alzheimer?s disease. Among the most important etiologies of periodontitis is Porphyromonas gingivalis, a keystone bacterial pathogen. A keystone pathogen can orchestrate inflammatory disease by remodelling a normally benign microbiota causing imbalance between normal and pathogenic microbiota (dysbiosis). The important characteristics of P. gingivalis causing dysbiosis is its virulence characteristics that causes effective subversion of host defenses to its advantage, allowing other pathogens to grow. However, the mechanisms involving these processes are poorly understood. Polymorphonuclear leukocytes (neutrophils) represent the primary cellular defense system in healthy oral tissues, but recent studies indicate that neutrophils can be involved in the initiation and progression of periodontitis when their function is subverted by periodontal bacteria. To date, most studies on the subversion of neutrophils by P. gingivalis have focused on integrins and complement mediated processes. However, various microbial strategies target host sialoglycoproteins for immune dysregulation. In addition, sialoglycans (sialic acid attached with carbohydrate component) on bacterial surface structures as well as virulence factors can also facilitate immune evasion leading to dysbiosis. The enzymes that break down sialoglycoproteins / sialoglycans are the ?sialoglycoproteases?, resulting in exposed terminal sialic acid. This process could lead to pathogen-toll like receptor (TLR) interactions mediated through sialic acid receptor - ligand mechanisms. Such a mechanism in P. gingivalis, needs to be clarified. The P. gingivalis genome codes for two sialoglycoproteases (PG-Sgps) (PG0778 & PG1724) [21], however, there is significant gap in understanding how on how PG-Sgps are involved in sialoglycan modifications and play a role in virulence and host immune response. Our preliminary data suggests that PG-Sgps can modify major virulence factors in P. gingivalis, and modulate virulence. We have also found unique sialogycans on P. gingivalis that may be important for such interactions. The objectives of this study are (i) to explore the functional role of PG-Sgps in virulence modulation by identifying specific sialoglycan variations in two important virulence determinants of P. gingivalis, and (ii) to study how PG-Sgps interact with neutrophils and influence the pathogenic potential of P. gingivalis. Our long term goal is to understand the role of PG-Sgps in manipulating innate immunity through sialic acid ligand binding interactions and how these interactions lead to immune subversion and dysbiotic inflammation. This study will provide options for disease intervention by identifying the sialic acid interacting ligands as potential drugs targets.

Public Health Relevance

Periodontitis is a chronic inflammatory condition leading to destruction of tooth-supporting structures resulting in tooth loss, as well as serious systemic health implications. Porphyromonas gingivalis a key stone pathogen has been shown to enable the emergence of dysbiotic oral bacterial communities by subverting host immune system, hence, play an important role in periodontal pathogenesis. The role of P. gingivalis sialoglycoproteases in modulating virulence and host immune interactions has not been studied so far. Fundamental knowledge of how P. gingivalis sialoglycoproteases affects pathogen and host modulations will aid in development of new therapeutic strategies leading to the improvement of oral health and also preventing periodontitis mediated consequences.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
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NIDR Special Grants Review Committee (DSR)
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Lunsford, Dwayne
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Loma Linda Veterans Assn Research & Education
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Sudhakara, Preethi; Gupta, Abishek; Bhardwaj, Anshumouli et al. (2018) Oral Dysbiotic Communities and Their Implications in Systemic Diseases. Dent J (Basel) 6: