Immune activation following cytomegalovirus infection: More important than direct viral effects in cardiovascular disease? (original) (raw)
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Enhanced Cytomegalovirus Infection in Atherosclerotic Human Blood Vessels
The American Journal of Pathology, 2004
Towne or low-passage clinical isolate and examined in situ for CMV cytopathic effect and immediate-early and early antigens, as indicators of active infection. At 5 to 7 days after inoculation, we found that CMV Towne actively infected eight of eight different atherosclerotic blood vessel explants (coronary artery, n ؍ 4; SV and IMA grafts, n ؍ 4), whereas it only infected 2 of 14 nonatherosclerotic blood vessel explants (SV, n ؍ 10; IMA, n ؍ 4) (P ؍ 0.001). The CMV clinical isolate actively infected none of six sets of nonatherosclerotic SV explants at 5 to 7 days after inoculation. The active CMV infections involved adventitial and, less frequently, intimal cells. A small subset of infected cells in atherosclerotic tissue expresses the endothelial cell marker CD31. Smooth muscle cells residing in both atherosclerotic and nonatherosclerotic blood vessels were free of active CMV infections even after all vascular tissue layers were exposed to the virus. In contrast, active CMV Towne infection was evident at 2 days after inoculation in smooth muscle cells and endothelial cells previously isolated from the SV tissues. We conclude that active CMV infection is enhanced in atherosclerotic blood vessels compared to atherosclerosis-free vascular equivalents, and this viral activity is restricted to subpopulations of intimal and adventitial cells. Experimental findings in animals and isolated human vascular cells, as well as some epidemiological studies in humans, support the hypothesis that human cytomegalovirus (CMV) may be a co-factor in atherosclerosis, 1-4 arterial restenosis, 5 acute arterial occlusion, 6 -8 and posttransplant coronary artery (CA) disease. 9,10 CMV might contribute to vascular disease by direct invasion of the blood vessel wall or by acting from distant sites through host-inflammatory response or perturbation of lipid metabolism. 11-13 Several investigators have reported that CMV nucleic acid is often present in walls of atherosclerotic arteries, 14 -19 implicating a role for CMV in directly initiating or advancing this disease. However, very little is known about the virus's ability to replicate within atherosclerosis-prone blood vessels, despite long-standing awareness of CMV's proclivity for replicating in and damaging small blood vessels and capillaries of persons with CMV disease. 20 Notably, rat CMV replicates in mechanically injured carotid arteries but not in healthy contralateral arteries of acutely infected rats, implying that preexisting vascular injury or inflammation can render large arteries conducive to viral replication. Endothelial cells (ECs) and smooth muscle cells (SMCs) that are isolated from human arteries and subsequently inoculated with CMV are able to support viral replication. The CMV replicative process disrupts cell-cycle control 16,24 and increases amounts or activities of procoagulant proteins, 25 reactive oxygen species, 26 -28 leukocyte adhesion molecules, 29 -32 cholesterol uptake and esterification, 33 cell motility, 34 and proinflammatory cytokines. 5,35-37 Thus, findings in isolated ECs and SMCs suggest multiple mechanisms by which CMV might promote atherogenesis and its complications.
Atherosclerosis, 2001
The possible contribution of cytomegalovirus (CMV) to pathogenetic events associated with atherosclerotic lesion establishment and progression is still controversial. We evaluated the possibility that active ongoing CMV infection could be correlated to evolution of unstable atheromatous lesion, by analyzing patients suffering from unstable angina (n = 61), acute myocardial infarction (n=43), stable angina (n= 26) and peripheral arteriopathy (n = 22) as compared to healthy subjects (n =30). Particularly, we assessed: past exposure to CMV by evaluating anti-CMV IgG antibodies; ongoing CMV infection by evaluating anti-CMV IgM antibodies and circulating interleukin (IL)-8 in serum; and CMV DNAemia in peripheral blood mononuclear cells (PBMC). Mean IgG values were significantly increased in patients from all groups, as compared to healthy subjects. CMV-specific IgM, as well as CMV DNAemia, were undetectable in both controls and patients. Circulating IL-8, significantly elevated in a group of individuals experiencing active CMV infection, was not significantly higher in cardiovascular disease patients, as compared to control subjects. These findings confirm previous evidence from the increased exposure to CMV infection in patients with atheromatous lesions. However, they provide further evidence against a direct implication of active systemic CMV infection in the pathogenesis of cardiovascular diseases, particularly those involving plaque instability.
Atherosclerosis, 2005
We have previously demonstrated that mouse cytomegalovirus (MCMV) infection aggravates atherosclerosis by stimulating the ongoing inflammatory process in the vascular wall. Here we investigated whether MCMV antigenic immune stimulation by UV-MCMV injection is sufficient to aggravate atherosclerosis. In addition we analyzed whether low viral doses are sufficient to stimulate atherosclerosis. Therefore, apoE −/− mice received a low dose injection with infectious virus (MCMV) or replication-deficient virus (UV-inactivated MCMV, UV-MCMV). Atherosclerosis progression, influx of inflammatory cells in atherosclerotic lesions and internal organs and the number of MCMV DNA copies in various organs were determined at 2 weeks after injection. After injection with infectious virus, MCMV DNA was present in internal organs, while no MCMV DNA could be detected after UV-MCMV injection. Interestingly, both MCMV and UV-MCMV significantly increased mean atherosclerotic lesion area and T cell number in the atherosclerotic lesions, while only MCMV infection increased T cell numbers in the internal organs. These data indicate that in apoE −/− mice both low dose infectious MCMV as well as MCMV antigenic injections are sufficient for atherosclerosis aggravation.
The American Journal of Pathology, 2010
Cytomegalovirus (CMV) persistently infects more than 60% of the worldwide population. In immunocompetent hosts , it has been implicated in several diseases , including cardiovascular disease , possibly through the induction of inflammatory pathways. Cardiovascular risk factors promote an inflammatory phenotype in the microvasculature long before clinical disease is evident. This study determined whether CMV also impairs microvascular homeostasis and synergizes with hypercholesterolemia to exaggerate these responses. Intravital microscopy was used to assess endothelium-dependent and-independent arteriolar vasodilation and venular leukocyte and platelet adhesion in mice after injection with either mock inoculum or murine CMV (mCMV). Mice were fed a normal (ND) or high-cholesterol (HC) diet beginning at 5 weeks postinfection (p.i.) , or a HC diet for the final 4 weeks of infection. mCMV-ND mice exhibited impaired endothelium-dependent vasodilation versus mock-ND at 9 and 12 weeks and endothelium-independent arteriolar dysfunction by 24 weeks. Transient mild leukocyte adhesion occurred in mCMV-ND venules at 7 and 21 weeks p.i. HC alone caused temporary arteriolar dysfunction and venular leukocyte and platelet recruitment , which were exaggerated and prolonged by mCMV infection. The time of introduction of HC after mCMV infection determined whether mCMV؉HC led to worse venular inflammation than either factor alone. These findings reveal a proinflammatory influence of persistent mCMV on the microvasculature , and suggest that mCMV infection enhances microvasculature susceptibility to both inflammatory and thrombogenic responses caused by hypercholesterolemia.
Scrutinizing role of Cytomegalovirus in the pathogenesis of atherosclerosis from early life
Pakistan Journal of Medical Sciences, 2013
Cytomegalovirus (CMV) is a successful ubiquitous virus, its prevalence is more than 60% among adult blood donors, worldwide. Contrary to this old concept, CMV infection is associated with the first leading cause of death among immune-competent hosts. This paradigm is getting stronger by the emergence of growing evidences about the role of CMV in the pathogenesis of various kinds of native and allo-atherosclerosis. Altered gene expression in vascular vessel wall due to the integrated viral genome to the host genetic material superimposes to the inflammatory pool activated by CMV antigenic substrates. Given the latent and persistent nature of CMV infection, modulation of immune system seems beneficial in partly prevention of atherosclerosis in nations. This goal might be achieved by in depth understanding of the joint links between CMV and pathogenesis of atherosclerosis from early life.
Circulation, 1999
Background-Previous studies suggest that infection may play a role in restenosis and atherogenesis; cytomegalovirus (CMV) is one of the implicated pathogens. To determine a potential causal role of CMV in these disease processes, we assessed whether CMV infection increases the neointimal response to injury of the rat carotid artery. Methods and Results-Carotid injury was performed on 60 rats; immediately thereafter, 30 rats were infected with rat CMV, and the other 30 were mock-infected. Six weeks later, rats were euthanized, and the salivary glands, spleen, and carotid arteries were harvested. CMV infection was associated with significant exacerbation of the neointimal response to injury (neointimal to medial ratio 0.81Ϯ0.59 versus 0.31Ϯ0.38 in CMV-infected versus control rats; PϽ0.0001). This occurred despite absence of infectious virus from vascular tissues and detection of CMV DNA by polymerase chain reaction in the injured artery only at day 3 after infection. Persistent distant infection, associated with systemic cytokine response, was evidenced by isolation of infectious virus from homogenates of both salivary glands and spleen and by higher serum levels of interleukin (IL)-2 and IL-4 (but not interferon-␥ and tumor necrosis factor-␣) in infected versus noninfected rats.
Microbes and Infection, 2004
Since the 1970s, cytomegalovirus (CMV) infection has been associated with atherosclerotic disease. However, the exact contribution of the virus remains uncertain. In this article we describe both a direct and indirect immune-mediated effect of the virus on the disease process. Eight-week-old apolipoprotein E (apoE) knockout mice were infected with mouse CMV (MCMV) or mock injected, and they were sacrificed at 2 and 20 weeks post-injection (p.i.) to study atherosclerosis, vascular wall IFNc and TNFa expression and MCMV spread. To study plasma IFNc and TNFa levels, blood was collected at 1, 2, 4 and 6 days p.i. in addition to days of sacrifice. Plasma cytokine levels were increased after MCMV infection at early time points and decreased to mock levels at 2 and 20 weeks p.i. At 2 weeks p.i., more aortic arch samples showed local cytokine expression after MCMV infection. The number of early atherosclerotic lesions and the percentage of mice containing early lesions were increased at 2 weeks p.i., while at 20 weeks p.i., the MCMV-induced effect on atherogenesis was seen on the late lesions. In conclusion, MCMV infection induces a systemic immune response reflecting an indirect effect of MCMV infection on atherosclerosis in addition to a local aortic immune response reflecting a direct effect of the virus on the atherosclerotic process.
Human Cytomegalovirus Seropositivity Is Associated With Impaired Vascular Function
Circulation, 2003
Background-Herpesvirus infection is a possible risk factor for atherogenesis, and diabetics may be at particular risk. Endothelial dysfunction is an early marker for atherosclerosis, and the present study tests the hypotheses that (1) prior infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) is associated with endothelial dysfunction and (2) this may be more marked in diabetics. Methods and Results-Serum samples were tested for anti-IgG antibodies to CMV and HSV from 400 subjects (mean age for diabetics and nondiabetics, 37.8Ϯ4.3 and 37.9Ϯ3.7 [SD]). We also assessed Helicobacter pylori and Chlamydia pneumoniae serology. Coronary atheroma was quantified by means of electron beam computed tomography. Subjects (nϭ157) underwent venous occlusion plethysmography with acetylcholine, bradykinin, glyceryl trinitrate, norepinephrine, and L-N G-monomethyl-L-arginine. Individuals who were seropositive for CMV had reduced responses to bradykinin (Pϭ0.005) and glyceryl trinitrate (Pϭ0.006). The reduced response to bradykinin remained significant (Pϭ0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (Pϭ0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics. Conclusions-This study shows that CMV-seropositive individuals have endothelial dysfunction and impaired responses to NO. This association was independent of conventional risk factors and may be associated with increased atherosclerosis burden. (Circulation. 2003;108:678-683.
Human cytomegalovirus infection and atherothrombosis
Journal of Thrombosis and Thrombolysis, 2012
Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intimamedia thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor jB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.