Chronic Active Herpes Simplex Type 2 Encephalitis in an Asymptomatic Immunocompetent Child

Brown, William D.; Bearer, Elaine L.; Donahue, John E.

doi:10.1177/0883073809353449

Cited by 10 publications

(6 citation statements)

References 32 publications

(95 reference statements)

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“…Emerging e pidemiological evidence links cognitive impairment with peaks in anti-HSV1 antibody titers in human serum [71] . More recently, chronic active HSV1 infection in the central nervous system has been reported [83] , lending additional credence to the idea that chronic active CNS infection may last late in life undetected, causing progressive damage. Correlations at the molecular level between genes associated with AD and cellular proteins involved in HSV1 infection are described, although direct experimental evidence is still lacking [84] .…”

Section: Discussionmentioning

confidence: 84%

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

et al. 2011

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Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/−6.7%) and travel together with APP inside living cells (81.1+/−28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/−0.2 to 0.3+/−0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/−0.1 to 0.4+/−0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 84%

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

et al. 2011

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“…Few reports of chronic HSE without prior acute infection include an infant with undefined perinatal infection [1] and a patient with asymptomatic HSV-2 infection [11]. Other cases suspicious of chronic HSE lacked etiologic confirmation by CSF PCR or histology [12,13].…”

Section: Resultsmentioning

confidence: 99%

Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient

et al. 2015

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“…Subsequently further support for the idea that a chronic low level of viral replication occurs and may damage the brain came from another study examining post-mortem brains for acute phase antibodies to HSV proteins (Wozniak et al, 2005). HSV re-activation in brain was proven in a study from an immuno-competent child infected at birth who underwent a brain biopsy for diagnosis of a cerebral mass found incidentally by radiology after a minor head injury at 8 years of age (Brown et al, 2010). HSV 2 was specifically identified by PCR from DNA in the biopsy.…”

Section: Hsv Infection and Alzheimer’s Diseasementioning

confidence: 99%

Herpes Simplex Virus, Alzheimer’s Disease and a Possible Role for Rab GTPases

Bearer

2019

Front. Cell Dev. Biol.

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Herpes simplex virus (HSV) is a common pathogen, infecting 85% of adults in the United States. After reaching the nucleus of the long-lived neuron, HSV may enter latency to persist throughout the life span. Re-activation of latent herpesviruses is associated with progressive cognitive impairment and Alzheimer’s disease (AD). As an enveloped DNA virus, HSV exploits cellular membrane systems for its life cycle, and thereby comes in contact with the Rab family of GTPases, master regulators of intracellular membrane dynamics. Knock-down and overexpression of specific Rabs reduce HSV production. Disheveled membrane compartments could lead to AD because membrane sorting and trafficking are crucial for synaptic vesicle formation, neuronal survival signaling and Abeta production. Amyloid precursor protein (APP), a transmembrane glycoprotein, is the parent of Abeta, the major component of senile plaques in AD. Up-regulation of APP expression due to HSV is significant since excess APP interferes with Rab5 endocytic trafficking in neurons. Here, we show that purified PC12-cell endosomes transport both anterograde and retrograde when injected into the squid giant axon at rates similar to isolated HSV. Intracellular HSV co-fractionates with these endosomes, contains APP, Rab5 and TrkA, and displays a second membrane. HSV infected PC12 cells up-regulate APP expression. Whether interference with Rabs has a specific effect on HSV or indirectly affects membrane compartment dynamics co-opted by virus needs further study. Ultimately Rabs, their effectors or their membrane-binding partners may serve as handles to reduce the impact of viral re-activation on cognitive function, or even as more general-purpose anti-microbial therapies.

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Chronic Active Herpes Simplex Type 2 Encephalitis in an Asymptomatic Immunocompetent Child

Cited by 10 publications

References 32 publications

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient

Herpes Simplex Virus, Alzheimer’s Disease and a Possible Role for Rab GTPases

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