Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune diseases, infectious diseases, neoplastic diseases, and inflammatory vascular plaque accumulation. The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce a chronic inflammatory response, although how these pathogens induce and maintain chronic inflammation is not well defined. The central hypothesis of this P01 is that pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders. To test this hypothesis we propose the following Aims:
Aim 1. To define the signaling pathways by which inflammatory mediators are induced in response to P. gingivalis and C. pneumoniae in endothelial cells, macrophages, and platelets.
Aim 2. To define the contribution of transcription factors in inflammatory responses to P. gingivalis and C. pneumoniae.
Aim 3. To define how P. gingivalis and C. pneumoniae stimulation of inflammatory mediators via these pathways modulates endothelial cell, platelet and macrophage function.
Aim 4. To define the role of these signaling pathways in the pathogenesis of P. gingivalis and C. pneumoniae induced thrombosis and chronic inflammation in a mouse model. The following Projects propose detailed studies to address these Aims: Project 1-The Role of Innate Immunity and Pathogen-Induced Inflammation in Platelet Function;Project 2-Innate Immune Defenses Against Acute and Chronic Infection with C. pneumoniae. Project 3- Innate Immunity, Lipid Signaling, and Chronic Infection. &Project 4- Innate Immune Mechanisms Involved in P. gingivalis-Induced Chronic Inflammation. The following Cores will service these Projects: A. Administrative Core, B. In Vitro Core, and C. Animal Core. These collaborative and synergistic studies 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. Furthermore, using defined animal models of inflammation we will characterize the roles of these innate immune pathways in inflammatory processes in vivo. Enhanced understanding of the roles of specific innate immune signaling pathways, which participate in proinflammatory mediator expression and functional immune responses will provide a promising avenue for novel therapies for chronic inflammatory disorders. PROJECT 1: THE ROLE OF INNATE IMMUNITY AND PATHOGEN-INDUCED INFLAMMATION IN PLATELET FUNCTION (FREEDMAN, J) PROJECT 1 DESCRIPTION (provided by applicant): 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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078894-04
Application #
8527669
Study Section
Special Emphasis Panel (ZAI1-PRJ-I (S1))
Program Officer
Minnicozzi, Michael
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$1,498,183
Indirect Cost
$142,016
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Shaik-Dasthagirisaheb, Yazdani B; Mekasha, Samrawit; He, Xianbao et al. (2016) Signaling events in pathogen-induced macrophage foam cell formation. Pathog Dis 74:
He, Xianbao; Liang, Yanmei; LaValley, Michael P et al. (2015) Comparative analysis of the growth and biological activity of a respiratory and atheroma isolate of Chlamydia pneumoniae reveals strain-dependent differences in inflammatory activity and innate immune evasion. BMC Microbiol 15:228
Beaulieu, Lea M; Clancy, Lauren; Tanriverdi, Kahraman et al. (2015) Specific Inflammatory Stimuli Lead to Distinct Platelet Responses in Mice and Humans. PLoS One 10:e0131688
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Huang, N; Shaik-Dasthagirisaheb, Y B; LaValley, M P et al. (2015) Liver X receptors contribute to periodontal pathogen-elicited inflammation and oral bone loss. Mol Oral Microbiol 30:438-50
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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
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
Kramer, Carolyn D; Weinberg, Ellen O; Gower, Adam C et al. (2014) Distinct gene signatures in aortic tissue from ApoE-/- mice exposed to pathogens or Western diet. BMC Genomics 15:1176

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