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Published on: June 11, 2017
Chronic non-vascular cytomegalovirus infection: effects on the neointimal response to experimental vascular injury
Y F Zhou1, M Shou, R F Harrell
1Washington Hospital Center, Vascular Biology Laboratory, Washington, DC, USA. yfz1@mhg.edu
Objective:
Epidemiologic and mechanistic evidence implicates a role for cytomegalovirus (CMV) in atherogenesis. Recently, we demonstrated that CMV has the capacity to causally contribute to atherogenesis; acute infection of rats with rat CMV (RCMV) 1 day after carotid artery injury increased neointimal accumulation. Importantly, in the injured vessel infectious virus could not be detected and viral genome was present only transiently, suggesting that additional mechanisms play a role in the virus-induced exacerbation of the vascular injury response other than the changes caused by direct infection of vessel wall cells. The present investigation was designed to determine whether chronic persistent RCMV infection, more relevant to the clinical situation, also exacerbates the response to injury and, if so, whether similar mechanisms are operative.
Methods:
Sixty 3-week-old male Spraque-Dawley rats received an i.p. injection of either 10(6) TCID50 RCMV (Priscott strain) or normal saline. The left carotid artery was balloon-injured 3 months after infection. Rats were killed 6 weeks later. This model produces persistent infection, as demonstrated by presence of infectious virus in the salivary glands at time of sacrifice.
Results:
The neointima to media (N/M) ratio of the injured vessel was 41% greater in the RCMV-infected than in control rats (1.40 +/- 0.48 vs. 0.99 +/- 0.45; P = 0.003). The aorta never contained infectious RCMV, and exhibited RCMV DNA, detected by PCR, only transiently. The persistent infection of non-vascular tissues was associated with increased serum levels of IL-2, IL-4 and IFN-gamma.
Conclusions:
CMV infection of young rats causes persistent infection of non-vascular tissues and increased cytokine levels. The neointimal response to subsequent vascular injury is increased, despite absence of virus from the vessel wall. These findings, as in acute infection following vascular injury, suggest that inflammatory and immune responses to chronic persistent CMV infection contribute to an exaggerated response to vascular injury.
Insights
Chronic cytomegalovirus (CMV) infection in rats exacerbates vascular injury responses. This suggests that inflammation and immune responses, not direct viral presence, drive increased atherosclerosis development.
Area of Science:
- Cardiovascular Research
- Infectious Diseases
- Immunology
Background:
- Cytomegalovirus (CMV) is implicated in atherogenesis.
- Previous studies showed acute CMV infection exacerbates vascular injury.
- The role of chronic CMV infection in this process requires further investigation.
Purpose of the Study:
- To determine if chronic persistent rat cytomegalovirus (RCMV) infection exacerbates the response to vascular injury.
- To investigate the mechanisms involved in virus-induced exacerbation of vascular injury.
Main Methods:
- Sixty rats were infected with RCMV or saline.
- Carotid arteries were balloon-injured 3 months post-infection.
- Vascular injury response was assessed 6 weeks later.
Main Results:
- RCMV-infected rats showed a 41% greater neointima to media ratio after injury.
- Infectious RCMV and transient RCMV DNA were not detected in the aorta.
- Persistent RCMV infection correlated with increased serum levels of IL-2, IL-4, and IFN-gamma.
Conclusions:
- Chronic RCMV infection leads to persistent non-vascular infection and elevated cytokine levels.
- The neointimal response to vascular injury is increased even without virus in the vessel wall.
- Inflammatory and immune responses to chronic CMV infection likely contribute to exaggerated vascular injury responses.
