Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

Abstract

Chlamydia pneumoniae is a common respiratory pathogen that is associated with an increased risk of cardiovascular disease. However, the mechanisms by which C. pneumoniae contributes to cardiovascular disease have not been determined yet. C. pneumoniae infection may accelerate the death of cells within atherosclerotic lesions and contribute to the formation of unstable lesions. To test this hypothesis, the impact of C. pneumoniae infection on the death of lipid-loaded mouse macrophages was investigated. It was observed that RAW 264.7 cells are highly susceptible to the toxic effects of oxidized low-density lipoprotein (LDL) and exhibit markers of cell death within 24 h of treatment with as little as 5 g/ml oxidized LDL. Subsequent infection with either live C. pneumoniae or heat-killed or UV-inactivated C. pneumoniae at a low multiplicity of infection for 24 to 72 h stimulated both additional binding of annexin V and the uptake of propidium iodide. Thus, C. pneumoniae augments the effects of oxidized LDL on cell death independent of a sustained infection. However, unlike oxidized LDL, C. pneumoniae infection does not activate caspase 3 or induce formation of the mitochondrial transition pore or the fragmentation of DNA, all of which are classical markers of apoptosis. Furthermore, primary bone marrow macrophages isolated from mice deficient in Toll-like receptor 2 (TLR-2) but not TLR-4 are resistant to C. pneumoniae-induced death. These data suggest that C. pneumoniae kills cells by a caspase-independent pathway and that the process is potentially mediated by activation of TLR-2.

Chlamydia Heat Shock Protein 60 Induces Trophoblast Apoptosis through TLR4

“…We repeated the same experiments in primary human placental fibroblasts and showed that pretreatment with pancaspase inhibitor, Z-VAD-FMK, blocked the cHSP60-induced apoptosis. These data support the findings of Yaraei et al (53) in RAW 264.7 cells and suggest that caspase-dependent and -independent pathways may play roles in cHSP60-induced apoptosis in trophoblasts.…”

“…Dumrese et al (52) have shown that C. pneumoniae infection of human aortic smooth muscle cells results in cell death with both apoptotic and necrotic characteristics. In addition, in RAW cells, infection with live C. pneumoniae or exposure to heat-killed or UV-inactivated C. pneumoniae led to aponecrosis, which was mediated via caspase-3-independent mechanisms (53). In a recent elegant review of Chlamydia pathogenesis, Byrne and Ojcius (54) state that "Chlamydia can elicit both the induction of host cell death, or apoptosis, under some circumstances and actively inhibit apoptosis under others.…”

Development potential of rifalazil and other benzoxazinorifamycins

“…Infection of vascular smooth muscle cells with C. pneumoniae resulted in the activation of a signal transduction profile that is typical of atherosclerosis and most probably mediated by transcription factor early growth response (EGR)-1 [87]. In the presence of LDL, C. pneumoniae can induce the formation of cholesterol-filled foam cells (an early marker of atherosclerotic lesions and oxidation of LDL) [87][88][89]. Cell destruction could result in local effects (i.e., in the vasculature) and could also result in a more generalised inflammatory response that is thought to be a risk factor in coronary heart disease (CHD) [87].…”

“…Cell destruction could result in local effects (i.e., in the vasculature) and could also result in a more generalised inflammatory response that is thought to be a risk factor in coronary heart disease (CHD) [87]. These effects could be mediated by Toll-like receptors [88,90]. It has also been suggested that other infectious agents (such as cytomegalovirus [91] and Porphyromonas gingivalis [90]) could play a role perhaps by acting synergistically with C. pneumoniae to promote atherosclerosis [91], although C. pneumoniae has been the primary focus in most of the cell-based or animal studies.…”

Chlamydia pneumoniaeAlters Mildly Oxidized Low‐Density Lipoprotein–Induced Cell Death in Human Endothelial Cells, Leading to Necrosis Rather Than Apoptosis

“…It is tempting to speculate that C. pneumoniae favors an oxLDL-induced necrotic commitment of the cells by way of increasing cellular stress and using bacterial caspase-independent mechanisms, such as the Bax activating pathway [1,8,10]. It was recently shown that subsequent C. pneumoniae infection of oxLDL-loaded macrophages augmented caspase-independent cell death [34]. Our data clearly indicate that infection of cells stimulated ROS production and, consequently, could increase the level of intracellular oxidized lipids known to be involved in oxidative stress-mediated cell death [15,18].…”