Bacterial invasion of vascular cell types: vascular infectology and atherogenesis

Abstract

To portray the chronic inflammation in atherosclerosis, leukocytic cell types involved in the immune response to invading pathogens are often the focus. However, atherogenesis is a complex pathological deterioration of the arterial walls, where vascular cell types are participants with regards to deterioration and disease. Since other recent reviews have detailed the role of both the innate and adaptive immune response in atherosclerosis, herein we will summarize the latest developments regarding the association of bacteria with vascular cell types: infections as a risk factor for atherosclerosis; bacterial invasion of vascular cell types; the atherogenic sequelae of bacterial presence such as endothelial activation and blood clotting; and the identification of the species that are able to colonize this niche. The evidence of a polybacterial infectious component of the atheromatous lesions opens the doors for exploration of the new field of vascular infectology and for the study of atherosclerosis microbiome.

Figure 1. Variety of avenues by which pathogens can contribute to atherogenesis

New insights on the plausible avenues that can be used by bacterial pathogens to initiate and maintain the focal inflammatory lesion that also involve inflammatory mediators and innate and adaptive immunity. The persistence of intracellular bacteria equals constant or repetitive injury that may ultimately lead to necrosis, plaque rupture, myocardial infarction or stroke. In white, contribution of bacteria as suggested by the latest data supporting the model, as discussed in this review. DC: Dendritic cell; HBP: High blood pressure; MI: Myocardial infarction.

Figure 2. 16S rRNA-specific DNA fragments in atheromata

The results of (A) the 16S rDNA PCR and (B) the 1.5 kb 16S rDNA-specific gel extracted bands as they appear after the run on the Agilent Bioanalyzer. The fragment analysis shows the absence of 16S-specific bands in the two healthy control tissue samples in the middle (H4 and H5), however, the amplicons that appear in the matching diseased D4 and D5 samples (at right end) are indicative of the presence of bacteria in these samples (A). This suggests an absence of bacterial DNA in healthy arterial tissues, #4 and 5. Reproduced from [Kalachikov S, Rafferty B, Kozarov E (2012), Manuscript in preparation].

Figure 3. Model of bacterial infection-mediated component of atherogenesis presenting a bacteremic and macrophage-mediated exacerbation of infection

Depicted are the tunica intima, a monolayer of ECs over a basal lamina and the tunica media containing SMCs. Represented on the left is the bacteremic microbial invasion of ECs. Within 24–72 h the invading intracellular bacteria turn into noncultivable state (in green). Endothelial activation is represented as a release in the vascular lumen of proinflammatory mediators such as MCP-1. The mediators activate circulating blood MNs and Mf, promote their local adhesion and diapedesis leading to transmigration into the lesion (in the center). Systemic Mf (on the left) can carry internalized persisting bacteria, thus contributing to the bacterial dissemination. The activation of noncultivable bacteria during vascular cell–cell transmission and the spreading of infection to adjacent ECs and to SMCs is shown on the left and right. Additional bacteria are released in the atherosclerotic core following apoptosis and necrosis of host cells (on the right). The phagocytosis of bacteria by a monocyte maturing into intimal tissue macrophage and the activation of dormant noncultivable bacteria into the active invasive stage (resuscitation, from green to red), following their internalization is shown in the center. Growth factors released from the phagocytes promote SMC proliferation and migration (neointimal formation). For clarity, only our novel paradigm suggesting the spreading, persistence in the dormant state and reactivation of bacteria within phagocytes as a root for chronicity of inflammation is depicted. For previously described mechanisms of atherogenesis such as endothelial activation, surface receptors, blood leukocyte transmigration, lipid uptake, foam cell formation, cell proliferation, vasa vasorum neovascularization, cell death, plaque rupture and blood coagulation/thrombus formation there are excellent visual presentations [128]. EC: Endothelial cell; Mϕ: Macrophage; MN: Monocyte; SMC: Smooth muscle cell.