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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lunsford, Dwayne
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University of Pennsylvania
Schools of Medicine
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Frost, L S; Dhingra, A; Reyes-Reveles, J et al. (2017) The Use of DQ-BSA to Monitor the Turnover of Autophagy-Associated Cargo. Methods Enzymol 587:43-54
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