Periodontitis is a chronic inflammatory disease that is driven by polymicrobial infection by red-complex periodontal pathogens, the best characterized of which is P. gingivalis (P.g.). To establish chronic infection in hostile host environments pathogens devise mechanisms by which they evade or subvert host defense mechanisms designed to eliminate them, one such mechanism is lysosome mediated degradation. We propose that P. gingivalis subverts phagolysosome degradation by hijacking the autophagosomal pathway to create a protective intracellular niche in macrophages. Specifically, we will test the hypothesis that upregulation of autophagosome formation is critical for P. gingivalis survival in macrophages and requires MREG mediated lysosomal maturation.
In specific aim 1 we will test the hypothesis that P. g. sequesters into autophagosomes and confers protection from lysosomal degradation.
In specific aim 2 we focus on how the mode of P. g. entry into macrophages contributes to its trafficking profile and persistence.
Specific aim 3 will focus on the LPS-TLR mediated signaling pathways contributing to lysosome maturation as it relates to autophagy.

Public Health Relevance

As sentinels of the immune system, macrophages function to eliminate pathogens through degradative processes as part of the host immune response. Numerous bacterial pathogens subvert these processes to persist, survive and in some cases replicate allowing for their dissemination thereby contributing to systemic disease. In these studies we will investigate the molecular mechanism by which a perio-pathogen, P.gingivalis evades the host defense mechanism by sequestration into none degradative compartments. Formation of these compartments requires a novel regulator of lysosome (degradative) function called melanoregulin. Understanding how melanoregulin contributed to pathogen degradation will allow us to develop therapeutic approaches to enhancing lysosome function during chronic infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022465-04
Application #
8837602
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2012-07-12
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gupta, Kshitij; Idahosa, Chizobam; Roy, Saptarshi et al. (2017) Differential Regulation of Mas-Related G Protein-Coupled Receptor X2-Mediated Mast Cell Degranulation by Antimicrobial Host Defense Peptides and Porphyromonas gingivalis Lipopolysaccharide. Infect Immun 85:
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Frost, Laura S; Lopes, Vanda S; Bragin, Alvina et al. (2015) The Contribution of Melanoregulin to Microtubule-Associated Protein 1 Light Chain 3 (LC3) Associated Phagocytosis in Retinal Pigment Epithelium. Mol Neurobiol 52:1135-1151
Shenker, Bruce J; Ojcius, David M; Walker, Lisa P et al. (2015) Aggregatibacter actinomycetemcomitans cytolethal distending toxin activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines. Infect Immun 83:1487-96
Frost, Laura S; Mitchell, Claire H; Boesze-Battaglia, Kathleen (2014) Autophagy in the eye: implications for ocular cell health. Exp Eye Res 124:56-66

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