Robust pro-inflammatory and lesser anti-inflammatory immune responses during primary simian varicella virus infection and reactivation in rhesus macaques

Simian varicella virus (SVV) infection of non-human primates models human varicella zoster virus (VZV) infection. Assessment of cell signaling immune responses in monkeys after primary SVV infection, after immunosuppression and during reactivation revealed strong pro-inflammatory responses and lesser anti-inflammatory components during varicella and reactivation. Pro-inflammatory mediators elevated during varicella included interferon-gamma (IFN-γ), interleukin (IL)-6, monocyte chemoattractant protein (MCP-1), interferon inducible T-cell α chemoattractant protein (I-TAC), interferon processing protein (IP-10), and anti-inflammatory interleukin-1 Receptor antagonist (IL-1Ra). After immunosuppression and at reactivation, levels of pro-inflammatory mediators MCP-1, eotaxin, IL-6, IL-8, MIF, RANTES (regulated-on-activation normal T-cell expressed and secreted), and HGF (hepatocyte growth factor) were elevated, as was the anti-inflammatory mediator IL-1Ra. Characterization of cytokine, chemokine and growth factor responses during different stages of varicella virus infection will facilitate immunotherapeutic and vaccine strategies.     

A case of intracranial saccular aneurysm after primary varicella zoster virus infection

We report a case of intracranial saccular aneurysm that developed 3 years after post-varicella ischemic stroke. A 6-year-old girl without apparent immunologic defects presented with right hemiparesis and expressive aphasia 1 month after chickenpox. Her magnetic resonance imaging scans revealed left basal ganglia infarction because of left lenticulostriate artery occlusion. Although her neurologic symptoms improved gradually, segmental irregular narrowing remained in the A1 and M1 segments of the left anterior and middle cerebral arteries, respectively. Three years later, the follow-up magnetic resonance angiography indicated saccular aneurysm in the anterior communicating artery and the anti-VZV IgG antibody index in the cerebrospinal fluid was elevated. Subclinical reactivation of VZV and the segmental vascular narrowing might cause intracranial aneurysm, even in immunocompetent children.     

Innate immune response to La Crosse virus infection

Viral encephalitis represents a significant, and costly, public health threat particularly for high-risk pediatric populations. An emerging mosquito-borne pathogen endemic to the United States, La Crosse virus (LACV) is one of the most common causes of viral encephalitis in children in the United States. However, no licensed therapeutics or vaccines currently exist for treatment. Hampering development efforts, the host response to LACV and its role in disease pathogenesis has only recently been examined. In this review, we discuss the current understanding of innate immune response in the context of viral pathogenesis and host susceptibility to LACV. In addition, we address the need for a clearer understanding of the early host–virus interactions in LACV infections as it relates to viral pathogenesis in the central nervous system.     

Localization of herpes simplex virus and varicella zoster virus DNA in human ganglia.

Human dorsal root ganglia from 14 randomly autopsied adults and 1 infant (all seropositive for both herpes simplex virus [HSV] and varicella zoster virus [VZV]) were examined for latent HSV-1 and VZV DNA by polymerase chain reaction. Thoracic ganglionic DNA from all subjects and trigeminal ganglionic DNA from 11 adults were analyzed. HSV-1 DNA was detected in trigeminal ganglia from 8 of 11 (73%) adults and in thoracic ganglia from 2 of 14 (14%) adults. VZV DNA was detected in trigeminal ganglia from 10 of 11 (91%) adults and in thoracic ganglia from 12 of 14 (86%) adults. None of the DNA samples were positive with primers specific for HSV-2. These findings indicate the presence of latent HSV-1 and VZV DNA in trigeminal ganglia and latent VZV DNA in thoracic ganglia of most seropositive adults. Furthermore, although HSV-1 latency most commonly develops in trigeminal ganglia, we also show for the first time the presence of HSV-1 latency in thoracic ganglia. Finally, both viruses can become latent in the same trigeminal ganglion.     

Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia

Varicella zoster virus (VZV), a human neurotropic alphaherpesvirus, becomes latent after primary infection and reactivates to produce zoster. To study VZV latency and reactivation, human trigeminal ganglia removed within 24 h after death were mechanically dissociated, randomly distributed into six-well tissue culture plates and incubated with reagents to inactivate nerve growth factor (NGF) or phosphoinositide 3-kinase (PI3-kinase) pathways. At 5 days, VZV DNA increased in control and PI3-kinase inhibitor-treated cultures to the same extent, but was significantly more abundant in anti-NGF-treated cultures (p = 0.001). Overall, VZV DNA replication is regulated in part by an NGF pathway that is PI3-kinase-independent.     

Granulomatous angiitis following primary varicella zoster infection

Granulomatous angiitis is an uncommon but well recognized complication of varicella zoster infection. The classic presentation is of a delayed hemiparesis in an often immunocompromised patient following zoster ophthalmicus. This report outlines the case of a young woman who developed a large left middle cerebral artery territory infarct secondary to granulomatous angiitis during primary varicella zoster infection.     

Cerebral vasculopathy associated with primary varicella infection

A previously healthy 5-year-old boy developed cerebral vasculopathy, presenting as two episodes of acute hemiparesis 3 and 9 months, respectively, after a primary varicella infection (chickenpox). This association has not been reported before, to our knowledge, although cerebral vasculopathy is a well-known complication of herpes zoster ophthalmicus. The diagnosis was based on the presence of oligoclonal varicella-specific IgG in the cerebrospinal fluid and angiographic findings. Clinical and angiographic follow-up, and serial thymidine kinase activity levels in the cerebrospinal fluid suggested a self-limiting course of the virus-induced vasculopathy. Varicella zoster virus seems to be another potential causative agent to be considered in acute childhood hemiplegia.     

Pathology of the human spinal ganglia in varicella-zoster virus infection

Spinal ganglia from a patient who died on the 6th day of varicella infection were examined by immunofluorescence and electron microscopy, and were compared with spinal ganglia from a patient dying on the 17th day of herpes zoster infection. In herpes zoster, typical intranuclear inclusion bodies were found in neurons, satellite cells and fibroblast-like cells of the ganglia, which contained numerous naked virus particles. In varicella, few changes were found by light microscopy but viral antigen was detected in a few neurons and satellite cells by immunofluorescence. Electron microscopy revealed scattered virus particles near the nuclear membrane of a neuron, satellite cells and capsular cells and enveloped particles in the cytoplasm of satellite cells. The particles in the nuclei were mostly naked virions with specific crescent-like inner-nuclear structure; those in the cytoplasm had complete and incomplete envelopes and showed pleomorphism. A "virus-like" intranuclear filament found in mononuclear cells in herpes zoster and a "plexiform vermicellar array" found in the nuclei of neurons in varicella are at present considered to be non-specific nuclear changes caused probably by viral infections.     

Elevated serum substance P during simian varicella virus infection in rhesus macaques: implications for chronic inflammation and adverse cerebrovascular events

Journal of NeuroVirology - Varicella and zoster, produced by varicella-zoster virus (VZV), are associated with an increased risk of stroke that may be due to persistent inflammation and...     

Review: The neurobiology of varicella zoster virus infection

Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys.     

Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms

A murine model of herpes simplex virus (HSV) infection was ussed to examine the role of the adrenal gland in restraint stress-induced suppression of viral immunity. Adrenal-dependent mechanisms were important for suppressing the generation of HSV-specific cytotoxic T lymphocytes (CTL) but not the associated diminished lymphadenopathy in response to local HSV infection. While exogenous corticosterone administration alone was unable to suppress lymphadenopathy and CTL generation in adrenalectomized mice, an adrenal-independent mechanism induced by restraints stress functioned in synergy with corticosterone to suppress lymphadenopathy and CTL development. These results suggest that both adrenal-dependent and independent mechanisms cotribute to stress-induced modulation of HSV immunity.     

Simian varicella virus infection of Chinese rhesus macaques produces ganglionic infection in the absence of rash

Varicella-zoster virus (VZV) causes varicella (chickenpox), becomes latent in ganglia along the entire neuraxis, and may reactivate to cause herpes zoster (shingles). VZV may infect ganglia via retrograde axonal transport from infected skin or through hematogenous spread. Simian varicella virus (SVV) infection of rhesus macaques provides a useful model system to study the pathogenesis of human VZV infection. To dissect the virus and host immune factors during acute SVV infection, we analyzed four SVV-seronegative Chinese rhesus macaques infected intratracheally with cell-associated 5 × 10³ plaque-forming units (pfu) of SVV-expressing green fluorescent protein (n = 2) or 5 × 10⁴ pfu of wild-type SVV (n = 2). All monkeys developed viremia and SVV-specific adaptive B- and T-cell immune responses, but none developed skin rash. At necropsy 21 days postinfection, SVV DNA was found in ganglia along the entire neuraxis and in viscera, and SVV RNA was found in ganglia, but not in viscera. The amount of SVV inoculum was associated with the extent of viremia and the immune response to virus. Our findings demonstrate that acute SVV infection of Chinese rhesus macaques leads to ganglionic infection by the hematogenous route and the induction of a virus-specific adaptive memory response in the absence of skin rash.