Date of Award


Document Type

On-Campus Dissertation

Degree Name

Doctor of Philosophy (PhD)


Molecular Sciences

Research Advisor

Gerald I. Byrne, Ph.D.


Robert Belland, Ph.D. John Cox, Ph.D. Edwards Park, Ph.D. Elaine Tuomanen, M.D.


Chlamydia pneumoniae, foam cell formation, atherosclerosis, TLR, LXR, MyD88, ABCA1


Chlamydia pneumoniae 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.

Data presented in this study have furthered our understanding of the different mechanisms of foam cell formation induced by C. pneumoniae and a variety of TLR agonists. I have shownthat C. pneumoniae 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.

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.