Biochemical and biophysical aspects of Chlamydia pneumoniae -exacerbated atherosclerosis

Date
2015
Authors
Evani, Shankar Jaikishan
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Abstract

Mechanical forces and tissue mechanical properties are critical components of living systems to maintain homeostasis and controlled physiological functions. These forces play a critical role in vascular pathologies including atherosclerosis. Various bacterial and viral organisms have been implicated in chronic or acute vascular inflammatory diseases. Of interest, is Chlamydia pneumoniae, an intracellular pathogen which causes bronchitis is highly implicated in the development of atherosclerosis. In this work, we have examined the interplay of infection and mechanical forces/properties of the tissue in disease development and progression using physiologically relevant in vitro models of infection. This work combines biomechanical and biochemical components during infection to gain insights into the pathophysiology of Chlamydia pneumoniae -exacerbated atherosclerosis, and is divided into three parts. In the first part of the study, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with Chlamydia pneumoniae . We found that shear-induced excessive inflammatory response by C. pneuomoniae -infected monocytes as measured the release of cytokines and chemokines, which contribute to localized 'hot spots' and exacerbated transendothelial infiltration of monocytes. In the second part, we show that C. pneumoniae infection of monocytes cause significant increase in the infected monocyte recruitment to the endothelium/E-selectin under physiological flow conditions due to altered membrane mechanics and the distribution of adhesion receptors, particularly CD44. Lastly, we elucidated the effect of C. pneumoniae-infected monocytes lodged in the subendothelial matrix on endothelial dysfunction and the changes in the biomechanical properties of the encapsulating collagen matrices due to extensive remodeling. Overall in this study, we have examined the effect of shear forces due to blood flow on the infected monocyte inflammatory response in vasculature, their recruitment to the site of pathology and eventual aberrations in mechanical properties of the vasculature caused by the lodged infected cells. As a whole this study highlights the important role of chlamydial infection, mechanical forces and tissue mechanics in atherosclerotic progression and provides insights into mechanical cues regulating the progression of atherosclerosis. Broadly, this study could possibly shed light on the physiology of chronic vascular inflammatory disease progression mediated by pathogens.

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Keywords
3D collagen, chlamydia pneumoniae, endothelium, rolling, shear stress, stiffness
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Department
Biomedical Engineering