The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce chronic inflammation. Epidemiological studies in humans and mouse models support a role for C. pneumoniae and P. gingivalis in chronic inflammatory plaque accumulation. IHowever, how these pathogens induce and maintain chronic inflammation is not well defined. Proinflammatory cytokines including IL-1B , TNF, and IL-6 play a critical role in chronic inflammation. It is known that human inflammatory vascular plaque is associated with polymorphisms in the IL-1 receptor antagonist gene and that IL-1 plays a role in bacterial induced inflammatory vascular plaque accumulation in mice. IL-1B polymorphisms are also associated with P. gingivalis mediated human inflammatory periodontal disease. In this project we will test the following hypotheses: 1) The induction of IL-1B occurs via a defined mechanism in endothelial cells which leads to stimulation of functional responses in platelets and macrophages;and 2) IL-1 plays a critical role in chronic oral inflammatory bone loss and inflammatory plaque formation that is associated with P. gingivalis chronic infection via cell specific mechanisms. To test these hypotheses we propose the following Aims:
Aim 1. To define the mechanism by which 1L1-B is induced in response to P. gingivalis in mouse endothelial cells and how IL-1 B modulates platelet and macrophage function.
Aim 2. To define the role of lL-1 and cell specificity in expression in P. gingivalis induced oral inflammatory bone loss in a mouse model.
Aim 3. To define the role of IL-1 and cell specificitv in expression in P. gingivalis induced chronic inflammation and plaque accumulation in a mouse model. Project 4 together with Projects 1- 3 will define the role of specific innate immune signaling molecules in P. gingivalis and C. pneumoniae induced inflammatory responses in cells relevant to chronic inflammatory processes, will characterize the roles of these innate immune pathways in inflammatory processes in vivo and define cell specificitv in these responses.

Public Health Relevance

The significance of this work is that it will define new mechanisms and signaling pathways in immune cells which functionally and collectively contribute to inflammatory pathways and will provide new mouse models for future studies. Enhanced understanding of the roles of innate immune signaling pathways and functional responses will ultimately provide a promising avenue for novel therapies for chronic inflammatory disorders.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI078894-05
Application #
8711213
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
Shaik-Dasthagirisaheb, Y B; Huang, N; Weinberg, E O et al. (2015) Aging and contribution of MyD88 and TRIF to expression of TLR pathway-associated genes following stimulation with Porphyromonas gingivalis. J Periodontal Res 50:89-102
Huang, Nasi; Gibson 3rd, Frank C (2014) Immuno-pathogenesis of Periodontal Disease: Current and Emerging Paradigms. Curr Oral Health Rep 1:124-132
Koupenova, Milka; Vitseva, Olga; MacKay, Christopher R et al. (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124:791-802
Shaik-Dasthagirisaheb, Yazdani B; Huang, Nasi; Gibson 3rd, Frank C (2014) Inflammatory response to Porphyromonas gingivalis partially requires interferon regulatory factor (IRF) 3. Innate Immun 20:312-9
Beaulieu, Lea M; Lin, Elaine; Mick, Eric et al. (2014) Interleukin 1 receptor 1 and interleukin 1? regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans. Arterioscler Thromb Vasc Biol 34:552-64
Clancy, Lauren; Freedman, Jane E (2014) New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis 37:12-6
Freedman, Jane E (2014) Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. Circ Res 114:1372-3
He, Xianbao; Berland, Robert; Mekasha, Samrawit et al. (2013) The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism. PLoS Pathog 9:e1003569
Freedman, Jane E; Tanriverdi, Kahraman (2013) Defining miRNA targets: balancing simplicity with complexity. Circulation 127:2075-7
Shaik-Dasthagirisaheb, Y B; Huang, N; Baer, M T et al. (2013) Role of MyD88-dependent and MyD88-independent signaling in Porphyromonas gingivalis-elicited macrophage foam cell formation. Mol Oral Microbiol 28:28-39

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