While there is evidence that chronic inflammation and infection promotes plaque formation, acute infections are associated with a transient five-fold increased risk of unstable coronary and vascular syndromes caused by platelet dependent thrombosis. While many strains of bacteria induce platelet aggregation, the mechanisms by which bacteria stimulate platelets has had minimal investigation. In preliminary data utilizing comprehensive microarray analyses, and a large community cohort of almost 2,000 subjects, we found distinct patterns of platelet gene expression in patients with cardiovascular disease. While several TLRs were detected in platelets, the expression of TLR2 and IL1R in particular were increased in patients with cardiovascular disease. Importantly, the functionality of TLR in platelets was established as incubation of platelets with TLR2 ligands dose-dependently induced platelet activation and aggregation. In addition, we found enhanced platelet function and platelet-monocyte/neutrophil binding with C. pneumoniae infection in vivo, and P. gingivalis incubation. The central hypothesis of the overall program project is that "Pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders". The central hypothesis of Project 1 is that bacteria mediate pro-thrombotic and -inflammatory processes in platelets via innate immune pathways. To investigate this hypothesis, we propose the following Aims:
Aim 1. To define the role of TLR2 and IL-1R in C. pneumoniae and P. gingivalis enhanced platelet function.
Aim 2. To define C. pneumoniae and P. gingivalis mediated modulation of TLR2- and IL1R-dependent signaling pathways in platelets and NFkappaB-dependent transcription in megakaryocytes.
Aim 3. To define the role of TLR2 and IL-1 R in platelet specific responses to C. pneumoniae and P. gingivalis dependent thrombosis in vivo.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI078894-05
Application #
8711207
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
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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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