Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Salehiniya, Hamid; Cain, Matthew D.; Klein, Robyn S.

doi:10.1007/s13311-016-0443-5

Cited by 98 publications

(103 citation statements)

References 291 publications

(345 reference statements)

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“…Herpes simplex encephalitis (HSE), caused by the DNA virus HSV-1, is the most common acute, sporadic encephalitis in the United States and worldwide 91 . Arthropod-born viruses, or arboviruses, are another important cause of encephalitis 92 . West Nile virus (WNV), a positive sense RNA flavivirus, is the most widely distributed arbovirus worldwide, with cases reported on every continent but Antarctica 93 .…”

Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 99%

Infectious immunity in the central nervous system and brain function

2017

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Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.

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Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 99%

Infectious immunity in the central nervous system and brain function

2017

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“…Venezuelan equine encephalitis virus (VEEV) is a member of the Togaviridae family of positive-sense RNA alphaviruses, and naturally cycles between mosquitoes and rodents (enzootic cycle), or mosquitoes and horses (epizootic cycle) (Salimi et al, 2016). VEEV is considered an important zoonotic pathogen with several reported outbreaks in South and Central Americas, the latter of which have spread to North America (Morrison et al, 2008; Weaver et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection

Cain

Salehiniya

Gong

et al. 2017

Journal of Neuroimmunology

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Viral infections of the central nervous system (CNS) are often associated with blood-brain barrier (BBB) disruption, yet the impact of virus replication and immune cell recruitment on BBB integrity are incompletely understood. Using two-photon microscopy, we demonstrate that Venezuelan equine encephalitis virus (VEEV) strain TC83-GFP, a GFP expressing, attenuated strain with a G3A mutation within the 5′ UTR that is associated with increased sensitivity to type I interferons (IFNs), does not directly impact BBB permeability. Following intranasal infection of both wild-type and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1)-deficient mice, which fail to block TC83-specific RNA translation, virus spreads to the olfactory bulb and cortex via migration along axonal tracts of neurons originating from the olfactory neuroepithelium. Global dissemination of virus in the CNS by 2 days post-infection (dpi) was associated with increased BBB permeability in the olfactory bulb, but not in the cortex or hindbrain, where permeability only increased after the recruitment of CX3CR1+ and CCR2+ mononuclear cells on 6 dpi, which corresponded with tight junction loss and claudin 5 redistribution. Importantly, despite higher levels of viral replication, similar results were obtained in IFIT1-deficient mice. These findings indicate that TC83 gains CNS access via anterograde axonal migration without directly altering BBB function and that mononuclear and endothelial cell interactions may underlie BBB disruption during alphavirus encephalitis.

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“…Similar to WNV, JEV induces the expression of cytokines and chemokines in the brains of infected animals, and minocycline is protective against JEV-induced CNS disease (20). One notable difference between WNV and JEV is that WNV does not appear to infect microglia in vivo (21), whereas JEV does.…”

mentioning

confidence: 99%

Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

Seitz

Clarke

Tyler

2018

J Virol

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Flaviviruses account for most arthropod-borne cases of human encephalitis in the world. However, the exact mechanisms of injury to the central nervous system (CNS) during flavivirus infections remain poorly understood. Microglia are the resident immune cells of the CNS and are important for multiple functions, including control of viral pathogenesis. Utilizing a pharmacologic method of microglia depletion (PLX5622 [Plexxikon Inc.], an inhibitor of colony-stimulating factor 1 receptor), we sought to determine the role of microglia in flaviviral pathogenesis. Depletion of microglia resulted in increased mortality and viral titer in the brain following infection with either West Nile virus (WNV) or Japanese encephalitis virus (JEV). Interestingly, microglial depletion did not prevent virus-induced increases in the expression of relevant cytokines and chemokines at the mRNA level. In fact, the expression of several proinflammatory genes was increased in virus-infected, microglia-depleted mice compared to virus-infected, untreated controls. In contrast, and as expected, expression of the macrophage marker triggering receptor expressed on myeloid cells 2 (TREM2) was decreased in virus-infected, PLX5622-treated mice compared to virus-infected controls. As CNS invasion by flaviviruses is a rare but life-threatening event, it is critical to understand how brain-resident immune cells elicit protection or injury during disease progression. Microglia have been shown to be important in viral clearance but may also contribute to CNS injury as part of the neuroinflammatory process. By utilizing a microglial depletion model, we can begin to parse out the exact roles of microglia during flaviviral pathogenesis with hopes of understanding specific mechanisms as potential targets for therapeutics.

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Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Cited by 98 publications

References 291 publications

Infectious immunity in the central nervous system and brain function

Infectious immunity in the central nervous system and brain function

Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection

Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

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