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Supplement

Do Pathogens Accelerate Atherosclerosis?¹

Department of Molecular Microbiology and Immunology and The Vaccine and Gene Therapy Institute, Oregon Health Sciences University, Portland OR 97201, and ^* Department of Surgery, Oregon Health Sciences University, Portland OR 97201

²To whom correspondence should be addressed. E-mail: nelsonj{at}ohsu.edu.

	ABSTRACT

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Infection with the pathogens human cytomegalovirus (HCMV) or Chlamydia pneumonia (CP) is linked to the development of vascular disease, including atherosclerosis. The role of pathogens in vasculopathies has been controversial. However, animal models have demonstrated a direct link between infection with CP and herpesviruses and the development of vascular disease. Clinical studies have shown a direct association of HCMV and CP with the acceleration of vascular disease. This article will review the evidence supporting the role for CP and HCMV in the development of vascular disease and will suggest a potential mechanism for HCMV acceleration of the disease process. Vascular diseases are the result of either mechanical or immune-related injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and/or migration from the vessel media to the intima, which culminates in vessel narrowing. A number of in vitro and in vivo models have provided potential mechanisms involved in pathogen-mediated vascular disease. Recently, we have demonstrated that HCMV infection of arterial but not venous SMC results in significant cellular migration in vitro. Migration was dependent on expression of the HCMV-encoded chemokine receptors, US28, and the presence of the chemokines, RANTES or MCP-1. Migration involved chemotaxis and provided the first evidence that viruses may induce migration of SMC toward sites of chemokine production through the expression of a virally encoded chemokine receptor in infected SMC. Because SMC migration into the neointimal space is the hallmark of vascular disease, these observations provide a molecular link between HCMV and the development of vascular disease.

KEY WORDS: • Chlamydia pneumonia • human cytomegalovirus • vascular disease • atherosclerosis

	INTRODUCTION

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Cardiovascular disease remains the most common cause of death in the U.S. While atherosclerosis accounts for the majority of these deaths (1) , other vasculopathies, such as restenosis after coronary angioplasty and transplant vascular sclerosis (TVS)³, the hallmark lesion of chronic solid organ graft rejection, cause significant morbidity and mortality in humans (2) . Although the etiologies of each of these vascular disease processes have some differences, the pathogenesis and manifestations are similar, and the end result is vessel narrowing or occlusion, leading to diminished blood supply and end organ ischemia. There are many risk factors associated with vascular disease, including hypertension, chemicals/tobacco, hyperlipidemia, diabetes, immunological factors and infectious agents such as bacteria and viruses. The majority of each of these risk factors alone is present in a relatively small percentage of the population; by contrast, viruses including the herpesvirus, human cytomegalovirus (HCMV), and the gram-negative bacteria, Chlamydia pneumonia, are ubiquitous (60–100% and 50–70% of the population, respectively) (3 ,4) . Although the mechanisms of many of these vascular disease risk factors are known, the mechanisms linking viruses and bacteria to vascular disease are unclear. However, it is likely that these pathogens interplay with the various other risk factors to cause vascular disease and that those people in whom the pathogens are present without the other risk factors are protected from pathogen-induced injury. To significantly impact survival and prevent vascular disease, an understanding of the pathogen-associated mechanisms must be elucidated.

Endothelial cell injury is the first step in the development of vascular disease (Fig. 1 ). The response to injury involves the local release of growth factors, chemokines and cytokines, which promote monocyte/macrophage migration and platelet adherence to the injured site. Activated macrophages in conjunction with T-cells form the initial lesion of atherosclerosis, the fatty streak (5) . These sites become thrombogenic and are loci of platelet adhesion and smooth muscle cell (SMC) migration/proliferation. Important stimuli to the migration and proliferation of SMC are various growth factors, cytokines and chemokines, which, in response to injury, are produced by platelets, activated macrophages and endothelial cells. The aforementioned events, which are initiated by endothelial cell injury, culminate in the formation of a fibrous plaque composed of SMCs, foamy macrophages and T-cells embedded in a collagenous matrix of connective tissue, which intrudes into the lumen of the vessel, resulting in narrowing and ultimate vessel occlusion.

View larger version (73K): [in this window] [in a new window]   Figure 1. Vascular disease process. Endothelial cell injury is the first step in the development of vascular disease. The response to injury involves the local release of growth factors, chemokines and cytokines, which promote monocyte/macrophage migration and platelet adherence to the injured site. Activated macrophages in conjunction with T-cells form the initial lesion of atherosclerosis, the fatty streak (5) . These sites become thrombogenic and are loci of platelet adhesion and SMC migration/proliferation. Important stimuli to the migration and proliferation of SMC are various growth factors, cytokines and chemokines and are produced in response to injury by platelets, activated macrophages, and endothelial cells. The aforementioned events, which are initiated by endothelial cell injury, culminate in the formation of a fibrous plaque composed of SMC, foamy macrophages and T-cells embedded in a collagenous matrix of connective tissue, which intrudes into the lumen of the vessel resulting in narrowing and ultimate vessel occlusion.

	Epidemiological association of pathogens in atherosclerosis

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Many epidemiological studies have shown a more than twofold increase in vascular disease in cytolomegalovirus (CMV)-seropositive subjects (6 ,7) . While the strongest association of CMV in vascular disease is with the development of restenosis and TVS, an association exists with atherosclerosis as well (Table 1 ). Recently, Muhlestein et al. (10) have determined that CMV-seropositive individuals are two- to threefold more likely to develop coronary artery disease over seronegative subjects, especially when combined with elevated levels of the inflammatory marker C-reactive protein (CRP). In support of this association, HCMV antigens and nucleic acids have been detected in early lesions of diseased vessels (9 ,11 ,12 ,13) . For instance, a recent study found that 76% of patients with ischemic heart disease were positive for CMV DNA in their arterial wall (8) . In another recent study, up to 53% of carotid artery atherosclerotic lesions were positive for HCMV DNA (14) . In addition, in thoracic aorta sections, HCMV was frequently detected in fatty streaks and normal appearing areas of diseased vessels near intercostal artery openings, but were rarely found in late atherosclerotic plaques (Fig. 2 ) (15) . By DNA hybridization, endothelial cells and SMCs (in the subendothelium, intima and media) appear to be the primary sites of infection, suggesting that the vasculature may serve as a reservoir for CMV. An evolutionary advantage for infection of vascular cells is the broad dissemination of the virus throughout the host. Viral antigen–posititve endothelial cells and SMCs, lining the intima/media border, have been detected only in fatty streaks (15) . Debakey et al. (15) suggest that viral antigen positivity corresponds to the early phases of atherosclerosis. However, there exists no evidence as to whether CMV reactivation from latency precedes or follows this initial phase of atherosclerosis.

View larger version (57K): [in this window] [in a new window]   Figure 2. HCMV in the aorta. HCMV DNA is found in SMC and endothelial cells of normal areas of lesioned vessels and in fatty streaks. DNA-positive cells are less likely to be found in late atheroslcerotic plaques. Antigen-positive cells, which denote virus replication, have been found only in endothelial cells and SMC found in fatty streaks.

Epidemiological studies of Chlamydia pneumonia (CP) in vascular disease have suggested an association with CP seropositivity and the development of vascular disease (16 ,18) . CP has been associated with the development of coronary heart disease, carotid stenosis, thrombosis of the lower extremities and aortic aneurysms, but as yet has an unlikely association with the development of TVS and restenosis (17) (Table 1) . In proof of this association, CP has been detected in atherosclerotic plaques of the aorta, coronary, carotid, iliac and pulmonary arteries (17) . In a recent study involving removal of diseased carotid arteries from patients at autopsy, up to 41% of patients had CP DNA–positive atherosclerotic plaques (14) . While CP has an affinity toward atherosclerotic lesions, the bacteria are rarely found in normal vascular tissues, except occasionally in macrophages scattered throughout the vessel wall (Fig. 3 ) (17 ,19) . This finding suggests that monocyte/macrophage cells are involved in the dissemination of CP from the lungs to the vascular wall. Similar to HCMV, CP also infects SMCs and endothelial cells that are present in fatty streaks (17 ,19) . However, unlike CMV, CP is also present in late atherosclerotic lesions. CP infection of these late fibrous plaques may increase thrombolysis by reducing plaque stability, which has become evident because CP is abundant in ruptured atherosclerotic plaques (20) . However, the role of this pathogen in the acceleration of atherosclerosis and the kinetics of development are still unclear.

View larger version (61K): [in this window] [in a new window]   Figure 3. CP in the vasculature. CP infects SMC, endothelial cells and macrophages of fatty streaks and late atherosclerotic plaques, but only rarely is CP detected in macrophages found in normal-looking vessel sections.

	Animal models of pathogen-induced vascular disease

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HCMV.

While the association of HCMV with human vascular disease is provocative, the most compelling evidence that a herpesvirus infection plays a role in the disease process is exemplified in animal models. Marek’s disease virus (MDV), a herpesvirus that infects fowl, was the first etiologic agent found to induce atherosclerosis (21 ,22) . In chickens and Japanese quails, these atherosclerotic lesions demonstrated similar histological features to human atherosclerosis. Similar to what is hypothesized to occur in human CMV-induced atherosclerosis, MDV antigens are detected early in the vascular lesions and late in SMCs at the periphery of the plaque. The advent of mouse models of atherosclerosis has dramatically improved the ability to study lesion development. Crossing ApoE^-/- mice, which have an increased incidence of atherosclerosis due to high levels of LDL and VLDL (23) , with other genetically altered mice has been widely used to study the effects of host proteins in the lesion formation. The ApoE^-/- mouse model provides an excellent system to determine the role of pathogens in atherosclerosis. We and other groups (24) have determined that mouse CMV (MCMV) infection of ApoE^-/- mice accelerates the development of atherosclerosis even in the absence of a high-fat diet (Fig. 4 A). MCMV infection increases the frequency of lesion and the severity of the atherosclerotic plaques (Fig. 4B) . However, because ApoE^-/- mice spontaneously develop atherosclerosis, even on a normal diet, the role of CMV as an initiator or accelerator of atherosclerosis can be further studied using this model.

View larger version (58K): [in this window] [in a new window]   Figure 4. MCMV infection accelerates atherosclerosis in ApoE-/- mice. A, At 5 wk of age, five ApoE-/- mice were injected intraperitoneally (ip) with saline or MCMV smith strain (5 x 105 pfu). Mice were maintained on a regular diet. At 45 or 60 d postinfection (pi), mice were perfused with saline followed by 4% paraformaldehyde (PFA) in phophate-buffered saline. Mouse aortas were removed at the point of takeoff from the heart down to the iliac bifurcation. The aorta/iliac vessels were cut into five equal pieces (1 cm each) and fixed in formalin. The tissues were paraffin embedded and sectioned (10-µm sections 20 µm apart). The sections were then stained for elastic fibers with iron hematoxylin stain or stained with Hematoxylin & Eosin. Average lesions per mouse aorta were determined by counting the atherosclerotic lesions from 250 aortic sections per mouse (n = 5). B, Elastin stained sections of representative aortas from uninfected and MCMV-infected mice at both 45 and 60 d pi. MCMV infection increased the average number of mouse atherosclerotic lesions over saline injected controls at both 45 and 60 d pi.

In solid organ transplantation, infection with rat CMV (RCMV) accelerates TVS, (26 ,27) , which leads to graft failure. In a rat heart transplantation model of chronic rejection, we have demonstrated that acute infection with RCMV dramatically decreases the mean time to TVS and graft failure and also increases the degree of TVS in the graft vessels. Importantly, the effects of CMV on the acceleration of TVS are not organ specific but occur in a broad range of solid organ transplants, including heart, kidney, lung and small bowel. In our laboratory, we have shown that the CMV-induced acceleration of TVS observed in the heart transplantation model is paralleled in a small bowel transplant model of chronic rejection (29 ,30) . In both of these transplant models, the recipient alloreactive immune response is required for RCMV acceleration of TVS. We have shown this by creating tolerant bone marrow chimeras that, when receiving a small bowel or heart transplant in the presence of CMV infection, failed to develop TVS. These data suggest that the mechanism by which CMV accelerates TVS involves the inflammatory events that accompany the alloreactive response to the donor tissue. Application of these phenomena to other vascular diseases would suggest that similar inflammatory events are necessary for CMV acceleration of atherosclerosis and restenosis.

CP.

Both mouse and rabbit models have been used to study the effects of CP on atherosclerosis. As in humans, CP infection has a high affinity for atherosclerotic lesions in both rabbits and mice. Muhlestein et al. (31) and Fong et al. (32) have shown that CP infection increases intimal thickness and atherosclerosis in 30–40% of New Zealand white rabbits. Reinfected animals showed the greatest response, and the effect of CP on intimal thickening and atherosclerosis was prevented by treating the animals for 10 wk starting at 5 d post infection with the antibacterial agent azithromycin (32 ,33) . Interestingly, CP can induce inflammatory changes in the vasculature of normocholesterol rabbits with the early beginnings of atherosclerotic lesions (31 ,34) . Similarly, in mice, which are more resistant to atherosclerosis than rabbits, CP infection has also been shown to increase atherosclerosis but only when the animals are hypercholesterolemic (35) . Also similar to rabbit models, multiple reinfections are required to establish a persistent CP infection in the mouse vasculature. Azithromycin treatment in CP-infected ApoE^-/- mice failed to reduce CP-accelerated lesion formation when given 2 wk after the second CP infection (36) . These results suggest that early antibacterial therapy is necessary to prevent the effects of CP on atherosclerosis. CP-infected ApoE^-/- mice exhibit altered nitric oxide synthetase expression and endothelial function, which is one of the underlying mechanisms thought to be involved in the effect of CP on accelerating atherosclerosis (37) . Both the rabbit and mouse models will be critical in determining the mechanisms of CP in the acceleration of atherosclerosis.

	In vitro models of pathogen-enhanced atherosclerosis

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While in vivo animal models have provided solid evidence for the link between CMV and CP and the acceleration of vascular disease processes, in vitro models allow one to characterize the underlying molecular and cellular mechanisms associated with this link. In vivo and in vitro, HCMV and CP productively infect SMCs, macrophages, endothelial cells and fibroblasts, which are the cell types associated with vascular lesions (Table 1) . Both CMV and CP can modify host cellular functions. One of the first observations supporting a causal role for pathogens in atherosclerosis was the finding that arterial vessels from MDV-infected chickens showed increased lipid deposition (31 ,38 ,39) . The accumulation of lipids is thought to be both an initiator and accelerator of atherosclerosis plaque formation. Both CP and CMV alter the lipid metabolism of infected SMCs and macrophages (Table 2 ). Specifically, HCMV infection of monocytes increases their expression of the scavenger receptors, thus enhancing lipid deposition in those cells (40) . CP infection causes increased LDL uptake in murine macrophages, with a subsequent increase in foam cell development (41) . The ability of pathogens to increase lipid accumulation in macrophages and SMCs may be an important step in accelerating atherosclerosis.

Infection of SMC is a similar feature of both CP and CMV. SMC proliferation and migration from the media into the neointimal space is the hallmark of vascular lesion formation, which suggests that pathogen-mediated acceleration of vascular disease likely involves enhanced accumulation of SMCs in the lesion. A reduction in apoptosis caused by HCMV and CP infection of SMCs could lead to accumulation of these cells at sites of vascular injury. Importantly, Shenk et al. (46) have shown that CMV infection of HeLa cells inhibits TNF-–induced apoptosis. The HCMV immediate early proteins (IE1) of CMV bind and cytoplasmically sequester the tumor suppressor gene p53, which contributes to blocking apoptosis (13) . An additional mechanism of cellular accumulation occurs through increased SMC proliferation at the site of vascular injury. CP and CMV infection of endothelial cells induces the release of growth factors and cytokines and often confer increased ability of infected cells to respond to these stimuli (43) . For example, HCMV infection of endothelial cells increases expression of fibroblast growth factor and platelet-derived growth factor (PDGF)-BB, which are potent stimuli in SMC proliferation (47) . In addition, HCMV infection of rat SMC increases the expression of PDGF receptor, which may induce both proliferation and migration of these cells (48) . Furthermore, HCMV infection upregulates the expression of the CC-chemokine RANTES in SMCs and fibroblasts (49 ,50) . We have recently demonstrated that infection of human SMCs with HCMV induces migration, which is dependent on the expression of the virally encoded chemokine receptor US28 and the binding of the CC-chemokines RANTES or MCP-1 (50) . We hypothesize that HCMV infection enhances SMC migration preferentially toward sites of vascular injury because of expression in SMCs of the virally encoded chemokine receptor US28. The resulting SMC accumulation in the vessel intima leads to neointimal hyperplasia and vessel narrowing.

	Role of chemokines and chemokine receptors in vascular disease

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Chemokines (chemotactic cytokines) and their receptors play a major role in the development of vascular disease. Chemokines are a group of inducible cytokines that promote cellular migration and activation through binding to their respective G-protein–coupled receptors (GPCRs) (51) . The two major groups of chemokines are the CC- and the CXC- chemokines, which are classified based on the presence of an NH₂-terminal cysteine motif. The CC chemokines include MCP-1 and RANTES, which are produced during inflammation and act by attracting monocytes, T-cells and B-cells to these sites of initial inflammation. Chemokine binding also increases the cellular production of other cytokines and growth factors amplifying the inflammatory response. In addition to their role in chemoattraction, chemokines upregulate expression of integrins promoting cellular adhesion to vascular endothelium. The CC chemokines have been detected in human and experimentally induced animal model atherosclerotic plaques (52 ,53) . In addition, Krensky et al. (54) have shown that RANTES is highly expressed in kidney allografts of recipients undergoing chronic rejection when compared with native kidneys in patients who were chronically rejecting their heart allografts. These data suggest that the CC-chemokines play a major role in vascular disease. Animal models, especially genetically altered mice, have provided the most definitive evidence that these molecules play an important role in these disease processes. For example, when apolipoprotein E–deficient mice, which normally develop atherosclerosis on a high-fat diet, are genetically engineered to lack the CC-hemokine MCP-1 gene or its receptor (CCR2), there is a significant reduction in the degree of atherosclerosis (55 ,56) . In addition, RANTES has been detected in atherosclerotic plaques and is highly expressed in atherosclerotic lesions associated with heart transplant chronic rejection and vasculopathy (57) . Likewise, rat renal allografts undergoing chronic rejection expressed both MCP-1 and RANTES (58) , and MCP-1 expression is elevated and persists long term in chronically rejecting rat cardiac allografts (59) and in experimentally induced hypertensive rats. Using a rat cardiac transplantation model, we have recently determined that in RCMV infected graft recipients undergoing chronic rejection, CC-chemokine expression was accelerated and increased over uninfected recipients (Orloff, S. L., manusript in preparation). These data suggest that modulation of chemokine expression during the chronic rejection process after RCMV infection accelerates graft rejection.

	Herpesvirus-encoded chemokine receptors

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All of the members of the ß herpesviruses encode both CC- and CXC-chemokine receptor homologs (60 ,61 ,62) . For example, HCMV encodes four chemokine receptors, which have been designated UL33, US27, US28 (CC) and UL78 (CXC) (62) . In addition, the ß herpesviruses, HHV6 and HHV7, each encode UL12 (CC) and UL51 (CXC) chemokine receptors. The conservation of virally encoded chemokine receptors in herpesviruses suggests an important role for these molecules in the biology of these viruses. Although the majority of these viral GPCR homologs have been shown to be functional molecules through in vitro binding studies, the actual function(s) of these viral molecules in the context of viral infection has been difficult to assess because of the lack of relevant in vivo systems. However, these virally encoded chemokine receptors have many predicted functions, which are based on the known functions of their cellular homologs. One predicted function for these virally encoded molecules is cellular activation. Because CC-chemokine stimulation of the HCMV US28 gene product results in intracellular Ca²⁺ flux and activation of mitogen-activated protein kinase pathways (63) , a potential function of this GPCR is activation of cellular signaling pathways necessary for viral replication. While this hypothesis is plausible, the gene is clearly not necessary for replication in vitro, because deletion of US28 does not affect virus growth (64) . This observation does not preclude the importance of the gene in vivo, as deletion of the mouse and rat CMV CC-chemokine receptor homologs, M33 and R33, respectively, results in reduced virus in the salivary glands (54 ,65 ,66) compared with wild-type virus.

Another potential function for these virally encoded GPCRs is to evade the immune system by sequestering chemokines (67) . The HCMV-encoded chemokine receptors, US28 and US27, can act as a sink to bind and internalize CC chemokines, which may prevent host immune cell recruitment and surveillance. The third function attributed to virally encoded GPCRs is to enhance virus dissemination through the induction of cellular migration. Our recent data showing that US28 mediates SMC migration is the first to demonstrate the ability of virally encoded chemokine receptors to induce cellular movement. Infection of SMCs with HCMV induced their migration. This migration was cell-type specific and occurred in arterial SMCs but not in venous SMC, endothelial cells or fibroblasts. Infection with a recombinant HCMV containing a deletion of the US28 gene (HCMV-28) failed to induce SMC migration, confirming that US28 was necessary for HCMV-induced cellular migration. Migration of SMC infected with HCMV-28 was rescued by coinfection of cells with adenovirus vectors expressing US28. More importantly, expression of US28 alone in the presence of a CC chemokine (RANTES or MCP-1) induced migration of SMC, showing that US28 expression was sufficient for SMC migration. US28-induced SMC migration involved chemotaxis or directed migration in response to a chemokine gradient established by activated macrophages. We hypothesize that expression of viral GPCRs in SMC functions to mediate their migration toward sites of inflammation, which promotes the development of vascular lesions.

In summary, although the concept of pathogens in causing vascular disease has crested and waned, currently we are on the crest of a wave of in vivo and in vitro experiments that can elucidate the mechanisms of pathogen-induced vascular disease. Both HCMV and CP are ubiquitous in the human population existing in a chronic latent state and therefore have the potential to play critical roles in long-term chronic disease processes. In addition, both of these pathogens can be found in the walls of affected arteries and have been shown to modify the host cellular physiology to a pro-inflammatory state. While the pathogenesis of vascular disease is multifactorial, HCMV is likely an important contributor and we have identified a novel mechanism as to how virally encoded chemokine receptors participate in this process. Further studies involving the use of genetically altered CMV lacking CC-chemokine receptors are required to test the importance of these chemokine receptors in the development of vasculopathies.

	FOOTNOTES

 
¹ Presented as part of the symposium entitled "Emerging Role of Pathogens in Chronic Diseases Requiring Nutritional Intervention" given at the Experimental Biology 2001 Meeting held March 31—April 4, 2001 in Orlando, FL. This symposium was sponsored by the American Society for Nutritional Sciences and was supported in part by educational grants from Novartis Nutrition and Ortho McNeil. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editors for the symposium publication were Nikhil V. Dhurandhar, Wayne State University, Detroit, MI, and Lawrence J. Cheskin

³ Abbreviations: CMV, cytolomegalovirus; CP, Chlamydia pneumonia; CRP, C-reactive protein; GPCR, G-protein–coupled receptor; HCMV, human cytomegalovirus; MCMV, mouse CMV; MDV, Marek’s disease virus; PDGF, platelet-derived growth factor; RCMV, rat CMV; SMC, smooth muscle cell; TVS, transplant vascular sclerosis.

	LITERATURE CITED

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