Chlamydia pneumoniae, Toll-like Receptors and Pathogenesis of Atherosclerotic Heart Disease

<p><em>Chlamydia pneumoniae</em> is an obligate intracellular bacterial pathogen that induces macrophage foam cell formation, a hallmark of early atherosclerosis, in the presence of low-density lipoprotein (LDL). Toll-like receptors (TLRs) play a central role for macrophages to detect pathogens and elicit inflammatory responses.</p> <p>Data presented in this study have furthered our understanding of the different mechanisms of foam cell formation induced by <em>C. pneumoniae</em> and a variety of TLR agonists. I have shown<em></em>that <em>C. pneumoniae</em> elicits foam cell formation predominantly via TLR2 by examining macrophages from TLR2^–/– mice. TLR2, TLR4 and TLR7 agonists require exogenous LDL for foam cell formation, whereas a TLR3 agonist induces foam cell formation even in the absence of added LDL. TLR3, but not TLR2 and TLR4 agonists, decreases the gene expression of a cholesterol effluxer, suggesting that inhibition of cholesterol efflux may be sufficient to induce foam cell formation. In myeloid differentiation factor 88 (MyD88)-deficient macrophages, TLR4 and TLR3 agonists each induce foam cell formation in the absence of exogenous LDL, suggesting that MyD88-mediated signaling interferes with MyD88-independent foam cell formation. A synthetic liver X receptor (LXR) agonist (GW3965) enhances cholesterol efflux and reduces foam cell formation by TLR2, TLR4 and TLR7, but not TLR3.</p> <p>Collectively, these results indicate that TLR-mediated foam cell formation occurs via two pathways: one is mediated by MyD88, requires excess exogenous LDL and depends on enhanced lipoprotein uptake. The other is MyD88-independent, does not require high levels of exogenous LDL, but depends on homeostatic cholesterol uptake coupled with inhibition of cholesterol efflux. These results suggest that pathogen-induced TLR signaling contributes to foam cell formation and that TLR3 signaling elicits a potentially more damaging foam cell formation response than does signaling via other TLRs due to the simultaneous increase in modified LDL uptake coupled with a decrease in cholesterol efflux by the former but not the latter.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

On-Campus Dissertation

Discipline thesis:degree_discipline

Molecular Sciences

Year dc:date.available

2007

Author dc:creator

• Cao, Fei

Contributors dc:contributor

• Gerald I. Byrne, Ph.D.

• Chlamydia pneumoniae
• foam cell formation
• atherosclerosis
• TLR
• LXR
• MyD88
• ABCA1
• Bacteria
• Bacterial Infections and Mycoses
• Cardiovascular Diseases
• Diseases
• Female Urogenital Diseases and Pregnancy Complications
• Medicine and Health Sciences
• Organisms

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/385

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1390