Systemic bacterial infections elicit inflammatory response that can result in acute or chronic complications. Our current approach to this problem has largely been limited from static systems though it is now well established that the dynamics of blood flow can seriously influence cellular response. A clear demonstration of such an interaction is that atherosclerotic plaques are almost invariably found in regions of disturbed flow fields such as arterial bends or branch points. Of interest, multiple lines of evidence from in vitro experimental, seroepidemiological, histopathological, animal models and limited clinical interventional studies suggest that infection due to a common intracellular respiratory pathogen, Chlamydia pneumoniae is a highly likely risk factor for atherosclerosis. However, the mechanism is poorly understood. Thus, understanding the complex interaction between C. pneumoniae infection and blood flow at cellular and molecular levels is important in exploring options for anti-infective intervention in the prevention or treatment of cardiovascular diseases. We hypothesize that fluid shear stress modulates the risk of atherosclerosis due to C. pneumoniae infection. We will use a systems bioengineering approach to test our hypothesis as defined by the following three specific aims: (1) Evaluate the biochemical effects of C. pneumoniae infection and shear stress on monocytes;(2) Evaluate the biophysical effects of C. pneumoniae infection and shear stress on monocytes;and (3) Examine the effect of C. pneumoniae infection and shear stress on monocyte adhesion to endothelial cells (EC) and transmigration under flow conditions. Our studies should provide insights into mechanisms by which fluid flow plays a critical role in early stages of C. pneumoniae-exacerbated atherosclerosis. In a larger context, this proposal introduces a new paradigm in our approach to understanding systemic infection and inflammation.

Public Health Relevance

Chlamydia pneumoniae is a ubiquitous respiratory pathogen and has been implicated in atherosclerosis. The proposal seeks to establish the role of fluid flow in altering the cellular and molecular mechanisms by which C. pneumoniae infection may initiate atherosclerosis. Thus, our research will have implications in the development of novel anti-infective or, as yet unexplored, mechanobiologically-inspired therapies for cardiovascular diseases. In a larger context, our results will provide fundamental insights into the interplay between biomechanical and biochemical factors in vascular inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Enhancement Award (SC1)
Project #
1SC1HL112629-01A1
Application #
8078758
Study Section
Special Emphasis Panel (ZGM1-MBRS-7 (CG))
Program Officer
Fleg, Jerome
Project Start
2011-06-01
Project End
2016-03-31
Budget Start
2011-06-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$361,250
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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Evani, Shankar J; Ramasubramanian, Anand K (2016) Biophysical regulation of Chlamydia pneumoniae-infected monocyte recruitment to atherosclerotic foci. Sci Rep 6:19058
Evani, Shankar J; Dallo, Shatha F; Ramasubramanian, Anand K (2016) Biophysical and Biochemical Outcomes of Chlamydia pneumoniae Infection Promotes Pro-atherogenic Matrix Microenvironment. Front Microbiol 7:1287
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Srinivasan, Anand; Lopez-Ribot, Jose L; Ramasubramanian, Anand K (2015) Microscale microbial culture. Future Microbiol 10:143-6

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