Association of human herpesvirus-6B with mesial temporal lobe epilepsy

Julie Fotheringham, Donatella Donati, Nahid Akhyani, Anna Fogdell-Hahn, Alexander Vortmeyer, John D. Heiss, Elizabeth Williams, Steven Weinstein, Derek A. Bruce, William D. Gaillard, Susumu Sato, William H. Theodore, Steven Jacobson

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Background: Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. Methods and Findings: HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive - the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression. Conclusions: Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

Original languageEnglish (US)
Pages (from-to)848-857
Number of pages10
JournalPLoS Medicine
Volume4
Issue number5
DOIs
StatePublished - May 1 2007
Externally publishedYes

Fingerprint

Human Herpesvirus 6
Temporal Lobe Epilepsy
Astrocytes
Brain
Amino Acid Transport System X-AG
Glial Fibrillary Acidic Protein
Polymerase Chain Reaction
Viral DNA
Epilepsy
Herpesviridae Infections
Viral Antigens
Herpesviridae
DNA
Seroepidemiologic Studies
Sclerosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fotheringham, J., Donati, D., Akhyani, N., Fogdell-Hahn, A., Vortmeyer, A., Heiss, J. D., ... Jacobson, S. (2007). Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Medicine, 4(5), 848-857. https://doi.org/10.1371/journal.pmed.0040180

Association of human herpesvirus-6B with mesial temporal lobe epilepsy. / Fotheringham, Julie; Donati, Donatella; Akhyani, Nahid; Fogdell-Hahn, Anna; Vortmeyer, Alexander; Heiss, John D.; Williams, Elizabeth; Weinstein, Steven; Bruce, Derek A.; Gaillard, William D.; Sato, Susumu; Theodore, William H.; Jacobson, Steven.

In: PLoS Medicine, Vol. 4, No. 5, 01.05.2007, p. 848-857.

Research output: Contribution to journalArticle

Fotheringham, J, Donati, D, Akhyani, N, Fogdell-Hahn, A, Vortmeyer, A, Heiss, JD, Williams, E, Weinstein, S, Bruce, DA, Gaillard, WD, Sato, S, Theodore, WH & Jacobson, S 2007, 'Association of human herpesvirus-6B with mesial temporal lobe epilepsy', PLoS Medicine, vol. 4, no. 5, pp. 848-857. https://doi.org/10.1371/journal.pmed.0040180
Fotheringham J, Donati D, Akhyani N, Fogdell-Hahn A, Vortmeyer A, Heiss JD et al. Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Medicine. 2007 May 1;4(5):848-857. https://doi.org/10.1371/journal.pmed.0040180
Fotheringham, Julie ; Donati, Donatella ; Akhyani, Nahid ; Fogdell-Hahn, Anna ; Vortmeyer, Alexander ; Heiss, John D. ; Williams, Elizabeth ; Weinstein, Steven ; Bruce, Derek A. ; Gaillard, William D. ; Sato, Susumu ; Theodore, William H. ; Jacobson, Steven. / Association of human herpesvirus-6B with mesial temporal lobe epilepsy. In: PLoS Medicine. 2007 ; Vol. 4, No. 5. pp. 848-857.
@article{4c0ff77154154f6bb2c7b07382acb799,
title = "Association of human herpesvirus-6B with mesial temporal lobe epilepsy",
abstract = "Background: Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90{\%} seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. Methods and Findings: HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69{\%}) additional patients with MTLE and from zero of seven (0{\%}) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive - the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression. Conclusions: Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.",
author = "Julie Fotheringham and Donatella Donati and Nahid Akhyani and Anna Fogdell-Hahn and Alexander Vortmeyer and Heiss, {John D.} and Elizabeth Williams and Steven Weinstein and Bruce, {Derek A.} and Gaillard, {William D.} and Susumu Sato and Theodore, {William H.} and Steven Jacobson",
year = "2007",
month = "5",
day = "1",
doi = "10.1371/journal.pmed.0040180",
language = "English (US)",
volume = "4",
pages = "848--857",
journal = "PLoS Medicine",
issn = "1549-1277",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Association of human herpesvirus-6B with mesial temporal lobe epilepsy

AU - Fotheringham, Julie

AU - Donati, Donatella

AU - Akhyani, Nahid

AU - Fogdell-Hahn, Anna

AU - Vortmeyer, Alexander

AU - Heiss, John D.

AU - Williams, Elizabeth

AU - Weinstein, Steven

AU - Bruce, Derek A.

AU - Gaillard, William D.

AU - Sato, Susumu

AU - Theodore, William H.

AU - Jacobson, Steven

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Background: Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. Methods and Findings: HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive - the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression. Conclusions: Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

AB - Background: Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. Methods and Findings: HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive - the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression. Conclusions: Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

UR - http://www.scopus.com/inward/record.url?scp=34249653639&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249653639&partnerID=8YFLogxK

U2 - 10.1371/journal.pmed.0040180

DO - 10.1371/journal.pmed.0040180

M3 - Article

C2 - 17535102

AN - SCOPUS:34249653639

VL - 4

SP - 848

EP - 857

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 5

ER -