Astrocytes as targets for Venezuelan equine encephalitis virus infection

Schoneboom, Bruce A.; Fultz, M J; Miller, Thomas H.; McKinney, Leslie C.; Grieder, Franziska B.

doi:10.3109/13550289909029475

Cited by 51 publications

(45 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While NO clearly has antiviral activities, a high level of NO is toxic to neurons, and its antiviral effects can also be virus specific [206]. Consistently, high levels of NO was correlated with accelerated death in mice infected with VEEV [186], and its inhibition prolonged survival time in TBEV-, MVEV-, and VEEV-infected mice [204,206,207]. Alternatively, inflammatory responses can result in formation of reactive oxygen species, which, in turn, triggers neuronal death.…”

Section: Neuropathogenesis Of Arbovirusesmentioning

confidence: 85%

“…Activated astrocytes and microglia play an important role in inflammatory responses during natural infection with encephalitic flaviviruses, namely JEV [200], WNV [201], and TBEV [198], as well as encephalitic alphaviruses [186]. Upon activation, astrocytes and microglia release several chemokines and cytokines such as TNF-α, IL-6, C-X-C motif chemokine ligand (CXCL)10, chemokine (C-C motif) ligand 2, monocyte chemoattractant protein-1, RANTES, IFN-γ-induced protein 10, and matrix metalloproteinases [154,195,[202][203][204]. Elevated levels of matrix metalloproteinases disrupts BBB by degrading TJ proteins [203,205], allowing unrestricted entry of leukocytes into the brain, which further exacerbates neuroinflammation.…”

Section: Neuropathogenesis Of Arbovirusesmentioning

confidence: 99%

See 1 more Smart Citation

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

View full text Add to dashboard Cite

Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus-and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause.

show abstract

Section: Neuropathogenesis Of Arbovirusesmentioning

confidence: 85%

Section: Neuropathogenesis Of Arbovirusesmentioning

confidence: 99%

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

View full text Add to dashboard Cite

show abstract

“…Previous studies have demonstrated that the murine model is characterized by biphasic disease, which starts with the productive infection of lymphoid tissue and ends in the destruction of the CNS by viral replication and a "toxic" neuroinflammatory response (12,13,15,16,39,42,43). By the time encephalitis has developed in an infected mouse, the infectious virus is usually absent from the peripheral organs and blood (12,13,15,16,39,42,43). However, virus replicates to high titers in the brain, and mice die 5 to 7 days after infection due to fatal encephalitis, as previously demonstrated with ZPC738 (2, 31).…”

Section: Discussionmentioning

confidence: 99%

Replication and Clearance of Venezuelan Equine Encephalitis Virus from the Brains of Animals Vaccinated with Chimeric SIN/VEE Viruses

Paessler

Petrakova

et al. 2006

J Virol

100

View full text Add to dashboard Cite

Venezuelan equine encephalitis virus (VEEV) is an important, naturally emerging zoonotic pathogen. Recent outbreaks in Venezuela and Colombia in 1995, involving an estimated 100,000 human cases, indicate that VEEV still poses a serious public health threat. To develop a safe, efficient vaccine that protects against disease resulting from VEEV infection, we generated chimeric Sindbis (SIN) viruses expressing structural proteins of different strains of VEEV and analyzed their replication in vitro and in vivo, as well as the characteristics of the induced immune responses. None of the chimeric SIN/VEE viruses caused any detectable disease in adult mice after either intracerebral (i.c.) or subcutaneous (s.c.) inoculation, and all chimeras were more attenuated than the vaccine strain, VEEV TC83, in 6-day-old mice after i.c. infection. All vaccinated mice were protected against lethal encephalitis following i.c., s.c., or intranasal (i.n.) challenge with the virulent VEEV ZPC738 strain (ZPC738). In spite of the absence of clinical encephalitis in vaccinated mice challenged with ZPC738 via i.n. or i.c. route, we regularly detected high levels of infectious challenge virus in the central nervous system (CNS). However, infectious virus was undetectable in the brains of all immunized animals at 28 days after challenge. Hamsters vaccinated with chimeric SIN/VEE viruses were also protected against s.c. challenge with ZPC738. Taken together, our findings suggest that these chimeric SIN/VEE viruses are safe and efficacious in adult mice and hamsters and are potentially useful as VEEV vaccines. In addition, immunized animals provide a useful model for studying the mechanisms of the anti-VEEV neuroinflammatory response, leading to the reduction of viral titers in the CNS and survival of animals.Venezuelan equine encephalitis virus (VEEV) is an enveloped virus with a nonsegmented, positive-sense RNA genome of approximately 11.4 kb and belongs to the Alphavirus genus in the Togaviridae family. The 5Ј two-thirds of the genome contains four nonstructural proteins (nsP1 to nsP4) that form an enzyme complex required for viral replication (46-48). After release of the viral genome into the cytoplasm, a nonstructural polyprotein is translated directly from this RNA and utilized in the production of a full-length, negative-sense replicative RNA intermediate (45). The full-length RNA then serves as a template for the synthesis of positive-sense genomic RNA and for transcription of a subgenomic 26S RNA (46). The approximately 4-kb-long, subgenomic RNA corresponds to the 3Ј onethird of the viral genome and is translated into a structural polyprotein that is proteolytically cleaved into the capsid and the envelope glycoproteins E2 and E1 (34). Two hundred forty copies of the capsid protein enclose the genomic viral RNA to form an icosahedral nucleocapsid that buds from the plasma membrane, acquiring a lipid envelope with embedded protein spikes formed by E1/E2 heterodimers (41, 48).Venezuelan equine encephalitis virus is a zoonotic pathogen...

show abstract

“…In general, the main target cells for alphavirus infection in the CNS are neurons, but infection of astrocytes by VEE also has been described (10,21,50). To determine the target cell for VEE in the CNS, we inoculated eGFP-VRP i.c.…”

Section: Discussionmentioning

confidence: 99%

Replicon Particles of Venezuelan Equine Encephalitis Virus as a Reductionist Murine Model for Encephalitis

Schäfer

Whitmore

Konopka³

et al. 2009

J Virol

View full text Add to dashboard Cite

Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) were used to model the initial phase of VEE-induced encephalitis in the mouse brain. VRP can target and infect cells as VEE, but VRP do not propagate beyond the first infected cell due to the absence of the structural genes. Direct intracranial inoculation of VRP into mice induced acute encephalitis with signs similar to the neuronal phase of wild-type VEE infection and other models of virus-induced encephalitis. Using the previously established VRP-mRNP tagging system, a new method to distinguish the host responses in infected cells from those in uninfected bystander cell populations, we detected a robust and rapid innate immune response in the central nervous system (CNS) by infected neurons and uninfected bystander cells. Moreover, this innate immune response in the CNS compromised blood-brain barrier integrity, created an inflammatory response, and directed an adaptive immune response characterized by proliferation and activation of microglia cells and infiltration of inflammatory monocytes, in addition to CD4؉ and CD8 ؉ T lymphocytes. Taken together, these data suggest that a naïve CNS has an intrinsic potential to induce an innate immune response that could be crucial to the outcome of the infection by determining the composition and dynamics of the adaptive immune response. Furthermore, these results establish a model for neurotropic virus infection to identify host and viral factors that contribute to invasion of the brain, the mechanism(s) whereby the adaptive immune response can clear the infection, and the role of the host innate response in these processes.

show abstract

Astrocytes as targets for Venezuelan equine encephalitis virus infection

Cited by 51 publications

References 67 publications

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Replication and Clearance of Venezuelan Equine Encephalitis Virus from the Brains of Animals Vaccinated with Chimeric SIN/VEE Viruses

Replicon Particles of Venezuelan Equine Encephalitis Virus as a Reductionist Murine Model for Encephalitis

Contact Info

Product

Resources

About