ABSTRACT
Varicella zoster virus (VZV) is a ubiquitous, human alphaherpesvirus that produces varicella on primary infection then becomes latent in ganglionic neurons along the entire neuraxis. In elderly and immunocompromised individuals, VZV reactivates and travels along nerve fibers peripherally resulting in zoster. However, VZV can also spread centrally and infect cerebral and extracranial arteries (VZV vasculopathy) to produce transient ischemic attacks, stroke, aneurysm, sinus thrombosis and giant cell arteritis, as well as granulomatous aortitis. The mechanisms of virus-induced pathological vascular remodeling are not fully elucidated; however, recent studies suggest that inflammation and dysregulation of programmed death ligand-1 play a significant role.
Subject(s)
Chickenpox , Herpes Zoster , Herpesvirus 3, Human/pathogenicity , Stroke/etiology , Animals , Chickenpox/complications , Chickenpox/immunology , Chickenpox/virology , Herpes Zoster/complications , Herpes Zoster/immunology , Herpes Zoster/virology , Humans , Stroke/virologyABSTRACT
Upon reactivation, varicella zoster virus (VZV) spreads transaxonally, infects cerebral arteries and causes ischemic or hemorrhagic stroke, as well as aneurysms. The mechanism(s) of VZV-induced aneurysm formation is unknown. However, matrix metalloproteinases (MMPs), which digest extracellular structural proteins in the artery wall, play a role in cerebral and aortic artery aneurysm formation and rupture. Here, we examined the effect of VZV infection on expression of MMP-1, -2, -3, and -9 in primary human brain vascular adventitial fibroblasts (BRAFS). At 6 days post-infection, VZV- and mock-infected BRAFs were analyzed for mRNA levels of MMP-1, -2, -3 and -9 by RT-PCR and for corresponding total intra- and extracellular protein levels by multiplex ELISA. The activity of MMP-1 was also measured in a substrate cleavage assay. Compared to mock-infected BRAFs, MMP-1, MMP-3 and MMP-9 transcripts, cell lysate protein and conditioned supernatant protein were all increased in VZV-infected BRAFs, whereas MMP-2 transcripts, cell lysate protein and conditioned supernatant protein were decreased. MMP-1 from the conditioned supernatant of VZV-infected BRAFs showed increased cleavage activity on an MMP-1-specific substrate compared to mock-infected BRAFs. Differential regulation of MMPs in VZV-infected BRAFs may contribute to aneurysm formation in VZV vasculopathy.
Subject(s)
Adventitia , Cerebral Arterial Diseases , Fibroblasts , Herpes Zoster , Herpesvirus 3, Human/pathogenicity , Matrix Metalloproteinases/metabolism , Adventitia/metabolism , Adventitia/virology , Cell Culture Techniques , Cerebral Arterial Diseases/metabolism , Cerebral Arterial Diseases/virology , Fetus , Fibroblasts/metabolism , Fibroblasts/virology , Herpes Zoster/metabolism , Herpes Zoster/virology , Humans , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 9/metabolismABSTRACT
In varicella-zoster virus (VZV)-infected primary human brain vascular adventitial fibroblasts (BRAFs), levels of beta interferon (IFN-ß,) STAT1, and STAT2 transcripts as well as STAT1 and STAT2 protein were decreased. IFN-α transcript levels were increased but not secreted IFN-α protein levels. Compared to IFN-α-treated control results, in VZV-infected BRAFs, phosphorylated STAT1 did not translocate to the nucleus, resulting in impaired downstream expression of interferon-inducible antiviral Mx1. Overall, VZV interference with the type I interferon pathway may promote virus persistence in cerebral arteries.
Subject(s)
Fibroblasts/metabolism , Gene Expression Regulation , Herpesvirus 3, Human/genetics , Myxovirus Resistance Proteins/antagonists & inhibitors , STAT1 Transcription Factor/genetics , Adventitia/blood supply , Adventitia/metabolism , Adventitia/pathology , Adventitia/virology , Blood Vessels/metabolism , Blood Vessels/pathology , Blood Vessels/virology , Brain/blood supply , Brain/metabolism , Brain/pathology , Brain/virology , Fibroblasts/pathology , Fibroblasts/virology , Herpesvirus 3, Human/metabolism , Host-Pathogen Interactions , Humans , Interferon-alpha/genetics , Interferon-alpha/metabolism , Interferon-beta/genetics , Interferon-beta/metabolism , Myxovirus Resistance Proteins/genetics , Myxovirus Resistance Proteins/metabolism , Phosphorylation , Primary Cell Culture , Protein Transport , STAT1 Transcription Factor/metabolism , STAT2 Transcription Factor/genetics , STAT2 Transcription Factor/metabolism , Signal TransductionABSTRACT
Virological confirmation of varicella zoster virus (VZV) vasculopathy is provided by presence of virus in the cerebral arteries, frequently associated with inflammation. Yet, cerebral arteries from normal subjects have never been studied for VZV DNA or antigen. We analyzed 63 human cerebral arteries from 45 subjects for VZV DNA and antigen, control herpes simplex virus (HSV)-1 DNA and antigen, and leukocyte-specific CD45 antigen. No cerebral arteries contained VZV or HSV-1 DNA or antigen; eight arteries from seven subjects contained leukocytes expressing CD45. Thus, the presence of VZV antigen in cerebral arteries of patients with stroke is likely to be clinically significant.
