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Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

ABSTRACT: BACKGROUND:We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure varied against the background of MICB genotypes. METHODS:We examined Caucasian individuals from the sample we studied in our previous report (Prasad et al., 2007) (SZ, n=21 and HS, n=19). Whole brain voxelwise analysis of structural MRI scans was conducted using Statistical Parametric Mapping, ver 5 (SPM5). The impact of rs1051788 variation and HSV1 seropositivity on grey matter volumes was examined using regression models on the combined sample of cases and controls, and then within each diagnostic group. RESULTS:In the combined sample of cases and controls, we observed the main effects of HSV1 seropositivity and genotypes, and a significant joint effect of HSV1 seropositivity and genotype mainly in the PFC. The joint effect was more prominent among cases than among controls. DISCUSSION:Our observations suggest that rs1051788 and HSV1 seropositivity are associated individually and jointly with reduced PFC grey matter volume. The patterns of these associations differ by diagnostic status, and these factors explain only a "small" portion of the variance in the grey matter volume reductions.

SUBMITTER: Prasad KM

PROVIDER: S-EPMC2856756 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

Prasad Konasale M KM Bamne Mikhil N MN Shirts Brian H BH Goradia Dhruman D Mannali Vimal V Pancholi Krishna M KM Xue Bai B McClain Lora L Yolken Robert H RH Keshavan Matcheri S MS Nimgaonkar Vishwajit L VL

Schizophrenia research 20100206 1-3

<h4>Background</h4>We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure va ...[more]

PMID: 20138739

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Project description:Abstract Background D-amino acid oxidase activator (DAOA) gene, which plays a key role in glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. In this study, we aimed to investigate whether the variation of DAOA rs2391191 could be associated with alterations in white matter integrity in first episode schizophrenia patients, and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Methods Forty-six patients with first-episode schizophrenia and forty-nine sex, age and education-matched healthy controls underwent diffusion tensor imaging (DTI) and were genotyped for SNP DAOA rs2391191. Tract-based spatial statistics (TBSS) was used to delineate the major fiber tracts that showed significant group difference. Patients underwent pathophysiological assessments using Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function assessments were performed by Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). Results Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD) mainly spreading over corpus callosum and corona radiata compared with healthy controls (FWE-corrected p<0.05). Compared with patients carrying G allele, patients with AA genotype showed lower FA in body of corpus callosum, and higher RD in genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. But there were no significant FA or RD differences between two genotype groups in healthy controls. In patients carrying G allele, mean FA values in body of corpus callosum were positively correlated with working memory, mean RD values in genu of corpus callosum were negatively associated with speed of processing, working memory and composite score of MATRICS Consensus Cognitive Battery (MCCB), whilst there were no significant correlations found in AA homozygotes. Discussion Abnormal white matter integrity in corpus callosum and corona radiata were replicated among our sample of first episode schizophrenia. Genetic variation of DAOA rs2391191 was associated with this abnormality, with AA homozygotes showing less white matter integrity in corpus callosum. Our findings also suggested that rs2391191influenced the association between white matter integrity and cognitive function of schizophrenia patients. Such results might be due to the process of glutamatergic neurotransmission and mitochondrial function DAOA involves in as pinpointed by previous in vitro studies.

Project description:Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.

Dataset Information

Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

Publications

Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

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