Background-Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities.

Vasculopathies caused by varicella zoster virus (VZV) are indicative of a productive virus infection in cerebral arteries after either reactivation of VZV (shingles) or primary infection (chickenpox). VZV vasculopathy can cause ischaemic infarction of the brain and spinal cord, as well as aneurysm, subarachnoid and cerebral haemorrhage, carotid dissection, and, rarely, peripheral arterial disease. VZV vasculopathy in immunocompetent or immunocompromised individuals can be unifocal or multifocal with deep-seated and superficial infarctions. Lesions at the grey-white matter junction on brain imaging are a clue to diagnosis. Involvement of both large and small arteries is more common than that of either alone. Most patients have a mononuclear cerebrospinal fluid pleocytosis, often with red blood cells. Cerebrospinal fluid pleocytosis and rash are absent in about a third of cases. Anti-VZV IgG antibody in the cerebrospinal fluid is found more frequently than VZV DNA. In recent years, the number of recognised VZV vasculopathies has grown, and accurate diagnosis is important for the effective treatment of these disorders.

Varicella zoster virus (VZV) is an exclusively human neurotropic alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis. Years later, in association with a decline in cell-mediated immunity in elderly and immunocompromised individuals, VZV reactivates and causes a wide range of neurologic disease, including herpes zoster, postherpetic neuralgia, vasculopathy, myelopathy, retinal necrosis, cerebellitis and zoster sine herpete (Fig. 1). Importantly, many of these complications occur without rash. This article discusses the clinical manifestations, treatment, and prevention of VZV infection and reactivation; pathogenesis of VZV infection; and current research focusing on VZV latency, reactivation, and animal models. Clinical manifestations of primary varicella zoster virus infection VaricellaInitial infection with VZV results in chickenpox (varicella), which is typically seen in children 1 to 9 years of age [1]. Primary infection in adults is usually more severe and may be accompanied by interstitial pneumonia. Infection in immunocompromised individuals often causes severe, disseminated disease. Climate seems to affect the epidemiology of varicella. In most temperate climates, more than 90% of people are infected before adolescence [2-5] with an incidence of 13 to 16 cases per 1000 people per year [6][7][8]. In tropical climates, VZV infection occurs later in life and adults are more susceptible than children [9][10][11]. Varicella has a peak incidence in the late winter and spring [10,[12][13][14], and epidemics tend to occur every 2 to 5 years [12][13][14].Varicella is characterized by fever concurrent with a self-limiting rash on the skin and sometimes mucosa. Headache, malaise, and loss of appetite are also seen. The rash begins as macules, rapidly progresses to papules, followed by a vesicular stage and crusting of lesions. Crusts slough off after 1 to 2 weeks. VZV is highly infectious and transmission occurs by direct contact with skin lesions or by respiratory aerosols from infected individuals. Central nervous system complications include self-limiting cerebellar ataxia in 1 in 4000 cases [15], meningitis, meningoencephalitis, and vasculopathy [16]. Strokes may occur months after varicella

Macrophage accumulation is not only a characteristic hallmark but also a critical component of pulmonary artery (PA) remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Utilizing multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, as well as primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive Pas (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL4/IL13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation while complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, while deficiency in C/EBPβ or HIF1 attenuated fibroblast driven macrophage activation. These findings challenge the current paradigm of IL4/IL13-STAT6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPβ signaling is critical for macrophage activation and polarization. Thus, targeting IL6 signaling in macrophages by completely inhibiting C/EBPβ, HIF1a or partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL6 and absent IL4/IL13 signaling.

Analysis of cells infected by a wide range of herpesviruses has identified numerous virally encoded microRNAs (miRNAs), and several reports suggest that these viral miRNAs are likely to play key roles in several aspects of the herpesvirus life cycle. Here we report the first analysis of human ganglia for the presence of virally encoded miRNAs. Deep sequencing of human trigeminal ganglia latently infected with two pathogenic alphaherpesviruses, herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV), confirmed the expression of five HSV-1 miRNAs, miR-H2 through miR-H6, which had previously been observed in mice latently infected with HSV-1. In addition, two novel HSV-1 miRNAs, termed miR-H7 and miR-H8, were also identified. Like four of the previously reported HSV-1 miRNAs, miR-H7 and miR-H8 are encoded within the second exon of the HSV-1 latency-associated transcript. Although VZV genomic DNA was readily detectable in the three human trigeminal ganglia analyzed, we failed to detect any VZV miRNAs, suggesting that VZV, unlike other herpesviruses examined so far, may not express viral miRNAs in latently infected cells.MicroRNAs (miRNAs) are a family of ϳ22-nucleotide (nt) noncoding RNAs that are capable of binding to specific target mRNAs and inhibiting their expression (reviewed in reference 1). They are typically derived from one arm of RNA stemloops found within noncoding regions of capped and polyadenylated transcripts (4, 26). Successive cleavage of these hairpin structures by the RNase III enzymes Drosha in the nucleus (25) and Dicer in the cytoplasm (7, 20) generates a miRNA duplex structure of ϳ20 bp with 2-nt 3Ј overhangs. One arm of this duplex is then loaded into the RNA-induced silencing complex (RISC), where it is used as a guide to target complementary transcripts for inhibition (19,28). In mammalian cells, miRNAs usually guide the RISC to imperfectly complementary target sites, resulting in the translational arrest of bound mRNAs and a modest but detectable mRNA destabilization (12,31,43).Due to their small size and nonimmunogenic nature, miRNAs appear ideally suited for use as regulatory molecules by viruses, and indeed, a number of human DNA viruses, including many herpesviruses, have now been reported to encode miRNAs (39). Herpesviruses can be divided into three subfamilies, the alpha-, beta-, and gammaherpesviruses, based on replication characteristics, genomic organization, and preferred latency sites. Members of all three subfamilies have been found to encode miRNAs, ranging from a low of 3 in the alphaherpesvirus herpes simplex virus 2 (HSV-2) (37, 38) to a high of 25 in Epstein-Barr virus (EBV) (5,17,33,46). The fact that all herpesviruses examined to date express miRNAs suggests that miRNAs play important roles in the herpesvirus life cycle, and several studies have in fact demonstrated the downregulation of cellular and/or viral mRNA targets by herpesvirus miRNAs (reviewed in reference 16).HSV-1 and varicella-zoster virus (VZV) are pathogenic human viruses both of which belong to ...