‘Infectious Burden’ – New Insights into Stroke Prevention
samples compared with normal control samples derived from autopsy samples in some17
but not all studies. Furthermore, specific
strains of H. pylori, such as those expressing cytotoxin gene A (CagA-positive), are believed to specifically contribute to the atherosclerotic process.18
Mechanisms of Pathogen-mediated Effects on Atherosclerosis
Direct infection of cells lining arterial walls can lead to changes in transcription profiles and regulatory pathways that can result in endothelial dysfunction, smooth-muscle proliferation or increased cytokine secretion.19
HSV1 infection of human arterial smooth-
muscle tissue causes decreased translation of cholesterol ester hydrolase messenger RNA (mRNA)20
and, furthermore, infection has
in rat models undergoing aortic allografts. In in vitro studies of human arterial smooth-muscle tissue, CMV has been shown to replicate for prolonged periods compared with shorter observed survival in human lung fibroblasts.25
been documented to interfere with the ability of cells to transport and metabolise cholesterol.21,22 vascular injury23 proliferation24
Pathogens may also exert non-specific effects on vessel walls, far removed from any localised infections. For example, research indicates that exposure early in life may be sufficient to pre- condition coronary arteries to atherosclerosis. A Swedish study of 175 autopsied children reported increased intima thickening in children with viral (32%) and bacterial (21%) infections compared with groups with no evidence of infection (16%).26
A case–control
study from the same group found increased intima-media thickness (IMT) in cases (0.48±0.02mm) compared with controls (0.41±0.02mm), while no difference between groups was observed during the acute phase of infection.27
One implication of this research is that
atherosclerosis may be a delayed sequela of an acute infection. Other studies of non-specific effects of chronic infection have focused on elevated levels of serum cytokines that may affect atheromatous plaque progression by influencing macrophage activity. In vitro studies have shown C. pneumoniae to induce cytokine secretion in infected mononuclear cells that can directly affect atheroma progression28
and induce macrophage conversion to foam cells, a critical aspect of atherosclerotic plaque progression.29
Pathogen infection can also increase the risk of pro-thrombotic events by altering platelet activation and dynamics with leukocytes. The P-selectin adhesion molecule is the most critical determinant of platelet activation. In vitro analysis of human platelets incubated with C. pneumoniae found an increased expression of P-selectin using flow cytometry and the initiation of widespread aggregation as measured by lumiaggregometry.30
Host and Environmental Determinants of Risk An important consideration in evaluating IB and stroke is to account for potential confounding and interaction by host characteristics. Socioeconomic status (SES) may be associated with nutritional status, access to care and many other factors that determine the ability to evoke a successful immune response against a pathogen and clear an infection. Health-seeking behaviour may similarly confound the association. Socioeconomic disparities influence the seroprevalence of infection,37
and exposure to low education and
chronic pyschosocial stress may increase antibody titre responses. Developing evidence shows SES may influence immune responses through influence on cortisol levels.38
However, studies have shown
that pathogen burden may be an independent predictor of cortisol levels after adjusting for demographics and socioeconomic position (SEP) measures,38
although residual influence of SES may continue to shape observed associations. Platelet activation and
platelet–leukocyte aggregates were shown to be significantly elevated in recent stroke cases compared with controls of healthy employees.31
Evidence for an association between cumulative measures of infectious serologies (CMV, HSV1 and 2, hepatitis A virus [HAV], C. pneumoniae and H. pylori) and endothelial dysfunction was observed in a cross-sectional study of 218 patients undergoing coronary angiography.32
In this study, endothelial reactivity was
assessed by measuring constriction in response to intracoronary administration of acetylcholine, and those individuals with more
EUROPEAN NEUROLOGICAL REVIEW
Underlying host genetic factors can also influence immune susceptibility and inflammatory responses to infection. Risk of CAD in those infected with C. pneumoniae has been shown to be elevated in patients with particular interleukin-1 (IL-1) polymorphisms, but IL-1 serum levels were not specified.39
Polymorphisms in the TLR4 gene
have been demonstrated to increase risk of MI in the presence of infection as well.40
Chronic Infection – Single Pathogen Associations with Stroke
Several case–control and cross-sectional studies have found a positive association between C. pneumoniae antibody titres and stroke risk.41,42
For example, in data from the Northern Manhattan Study (NOMAS), 246 stroke cases were matched by age, sex and
35 CMV has been shown to induce and double the rate of smooth-muscle-cell
than four positive serologies had more vasoconstriction than those with fewer than four positive serologies.32
Another study, consisting
of stroke cases with self-reported infection with an exclusion provision for suspected post-infective stroke, found infection- exposed cases to have significantly higher P-selectin mean fluorescence units ± standard deviation (SD) (1.78±0.28 versus 1.49±0.36) and proportion of platelet–leukocyte aggregates (7.28±2.76 versus 4.96±2.58%) levels than those cases without a history of infection.32
Immune responses that target ‘self’ epitopes may be elicited by infection and have been implicated in atherogenesis. Heat-shock protein 60 (HSP60) is a highly conserved protein that is overexpressed in several cell types of atherosclerotic lesions.33,34 The ‘molecular mimicry’ hypothesis suggests that exposure to bacterial or virally encoded HSPs, homologous to the human variants, can elicit an immune response that will target both pathogen and self HSPs. Clinical studies have shown that increased antibody titres to homologous C. pneumoniae HSP65 are associated with elevated coronary calcium.35
An alternative pathway of infection-mediated atherosclerotic effects is through the toll-like receptor (TLR) proteins. Infection increases expression of TLR, activating nuclear factor kappa beta (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways that in turn set off a pro-inflammatory cascade.36
TLR proteins are overexpressed in
atheromatous plaque and may continue to be overexpressed post- infection even in the absence of the initiating pathogen.19
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