Interaction of host and microbes in the atherosclerotic plaques

Atherosclerosis is characterized by chronic inflammation and vascular cell proliferation. The intracellular bacterium Chlamydia pneumoniae has been implicated in atherogenesis as it has been recovered from atheromatous plaques. In vitro, C. pneumoniae infection initiates activation of the transcriptional factor NF-κB via small GTPases Rac1 and RhoA. This signaling cascade results in the synthesis of numerous proinflammatory and pro-coagulatory mediators (e.g., IL-6, IL-8, RANTES, MCP-1, PAI-1, TF) that are also characteristically produced in the plaque. In parallel, chlamydiae stimulate vascular cell proliferation via ERK 1/2 MAPkinase and transcription factor Egr-1. Thus, chlamydial infection may have a role in the inflammatory, as well as in the angiogenic, component of atherogenesis. The proinflammatory activity of chlamydial infection is reduced by statins, via suppression of Rho and Rac signalling, indicating a beneficial anti-inflammatory effect of lipid-lowering drugs in vascular infection. C. pneumoniae uses blood monocytes as transport vehicles for systemic dissemination. In monocytes the pathogen enters a non-replicative, but viable, state characterized by continuous production of mRNA transcripts. Release of proinflammatory mediators by circulating or transendothelially migrating infected monocytes might promote chronic inflammation and atherogenesis. Interestingly, persistent chlamydiae in monocytes appear to be refractory to conventional antichlamydial treatment, thus posing a challenge to the ongoing experimental treatment studies. The persistent state is likely to have a key role in the pathogenesis of chronic chlamydial infections and requires further examination on a molecular level.