HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels.

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

Frequency of retrotransposon human endogenous retrovirus-K113 and a preliminary analysis of some microbial clues in bipolar disorder.

Aim: The aim of our study was to investigate whether the retrotransposon human endogenous retrovirus (HERV)-K113 could be related with bipolar disorder or not. As a second and a preliminary aim, we also conducted bacterial screening in whole blood in a limited number of samples. Patients & methods: Three separate PCR reactions including the preintegration sites and sites within the viral sequences were performed for HERV-K113 detection. Bacterial screening was performed with SSCP/sequencing analysis. Results & conclusion: No difference was observed in terms of the frequency of retrotransposon HERV-K113 in Turkish bipolar disorder patients and healthy controls. SSCP/sequencing and alignment analysis for bacterial screening reflected the possible presence of different bacteria. We strongly recommend the broadened retrotransposon and microbial diversity analyses in bipolar disorder for future studies.

The association between antibodies to neurotropic pathogens and bipolar disorder : A study in the Dutch Bipolar (DB) Cohort and meta-analysis.

Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567-1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437-1.761], CMV [adjusted OR 0.884 95% CI 0.603-1.295], EBV [adjusted OR 0.968 95% CI 0.658-1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672-1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95-1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10-2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.

Assessment of cognitive impairment in HSV-1 positive schizophrenia and bipolar patients: Systematic review and meta-analysis.

A common characteristic among schizophrenia and bipolar disorder patients is cognitive dysfunction, especially for memory and attention. Recent evidence has suggested that cognitive impairment in schizophrenia and bipolar disorder patients could be associated with herpes simplex virus 1 (HSV-1) infection, due to the ability of HSV-1 to infect neurons in the temporal lobe, which plays a key role in the formation of memory and processing of sensory input. The objective of this review is to analyze the aggregate neuropsychological testing data from previous studies regarding the impact of HSV-1 infection on cognitive function in schizophrenia and bipolar disorder. A systematic literature search generated a total of 379 articles; 12 full-text case control and cross-sectional studies met the eligibility criteria to be included in the review. Pooled effects assessed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scores and the three index scores for immediate memory, delayed memory, and attention in a random effects model. The overall effect for RBANS total score was in favor of the HSV-1 positive group (z = 3.10, p = 0.002). A statistically significant overall effect of cognitive impairment for memory and attention indices was in favor of HSV positive schizophrenia patients (z = 5.95 p < 0.00001). The findings from the meta-analysis suggest that serological evidence of HSV-1 infection has a significant impact on cognitive function with small to moderate effect sizes (-0.23 to -0.49), particularly affecting memory and attention, in schizophrenia and bipolar patients.

Transcription of human endogenous retroviruses in human brain by RNA-seq analysis.

BACKGROUND: Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. Increased levels of transcripts from the W and H families of HERV have been observed in association with human diseases, such as multiple sclerosis and schizophrenia. Although HERV transcripts have been detected in many tissues and cell-types based on microarray and PCR studies, the extent of HERV expression in different cell-types and diseases state has been less comprehensively studied. RESULTS: We examined overall transcription of HERV, and particularly of HERV-W and HERV-H elements in human postmortem brain samples obtained from individuals with psychiatric diagnoses (n = 111) and healthy controls (n = 51) by analyzing publicly available RNA sequencing datasets. Sequence reads were aligned to prototypical sequences representing HERV, downloaded from Repbase. We reported a consistent expression (0.1~0.2% of mappable reads) of different HERV families across three regions of human brains. Spearman correlations revealed highly correlated expression levels between three brain regionsacross 475 consensus sequences. By mapping sequences that aligned to the consensus sequences of HERV-W and HERV-H families to individual loci on chromosome 7, more than 60 loci from each family were identified, part of which are being transcribed. The ERVWE1, locus located at chr7q21.2, exhibited high levels of transcription across the three datasets. Notably, we demonstrated a trend of increased expression of overall HERV, as well as HERV-W family in samples from both schizophrenia and bipolar disorder patients. CONCLUSIONS: The current analyses indicate that RNA sequencing is a useful approach for investigating global expression of repetitive elements, such as HERV, in the human genome. HERV-W/H with the tendency of transcription up-regulation in patients suggests potential implication of HERV-W/H in psychiatric diseases.

[Implication of human endogenous retroviruses in schizophrenia and bipolar disorder]. / Les rétrovirus endogènes humains, une implication dans la schizophrénie et le trouble bipolaire.

Schizophrenia and bipolar disorder are neuropsychiatric disorders of unknown origin. It seems that these two disorders share some common etiopathogenic mechanisms including genetic, environmental and inflammatory ones. Reactivation of the human endogenous retrovirus type W (HERV-W) can be a shared element in the pathophysiology of schizophrenia and bipolar disorder, linked to immuno-genetic and environment risk factors. We will present studies that have highlighted the presence of HERV-W in schizophrenic and bipolar disorder patients. We will then describe a two-hit model which could explain the common pathophysiological mechanism of affective and non-affective psychosis. Identification of immuno-inflammatory mediated subgroup of schizophrenia and bipolar disorder associated to HERV-W reactivation might open the way for the development of diagnostic biomarker and more targeted treatments. These new tools pave the way towards personalized psychiatry for a better care of patients.

Infection and inflammation in schizophrenia and bipolar disorder.

The present study investigated the relationship between exposure to infectious agents and inflammation markers in individuals with schizophrenia (SZ), bipolar disorder (BP), and controls without a psychiatric disorder. We measured plasma levels of antibodies and innate immune markers and correlated them with clinical symptoms and cognitive function. In both SZ and BP, we found an increase in soluble CD14, and in BP an increase in C-reactive protein, IgM class antibodies against cytomegalovirus (CMV), and IgG class antibodies against herpes simplex virus 2. Furthermore in BP, we observed a negative relationship between IgG antibodies against CMV and scores for cognitive function.

HIV-infection and psychiatric illnesses - A double edged sword that threatens the vision of a contained epidemic: The Greater Stockholm HIV Cohort Study.

CONTEXT: The Greater Stockholm HIV Cohort Study is an initiative to provide longitudinal information regarding the health of people living with HIV. OBJECTIVE: Our aim was to explore the prevalence of HIV and its association with psychiatric co-morbidities. DESIGN, SETTING AND PARTICIPANTS: All patients with a recorded diagnosis of HIV (any position of the ICD-10 codes B20-B24) were identified during the period 2007-2014 and related to the total population in Stockholm by January 1, 2015, N = 2.21 million. The age at diagnosis, gender, and first occurrence of an HIV diagnosis was recorded. Analyses were done by age and gender. Prevalence of psychiatric co-morbidities amongst HIV patients were recorded. MAIN OUTCOME MEASURES: Age-adjusted odds ratios with 95% confidence intervals were calculated with logistic regression for prevalent psychiatric co-morbidities in HIV infected individuals compared to the prevalence in the general population. RESULTS: The total prevalence of HIV was 0.16%; females 0.10% (n = 1134) and males 0.21% (n = 2448). HIV-infected people were more frequently diagnosed with psychiatric illnesses and drug abuse. In females and males with HIV-diagnosis respectively, drug dependence disorder was 7.5 (7.76% vs 1.04%) and 5.1 (10.17% vs 1.98%) times higher, psychotic disorders were 6.3 (2.65% vs 0.42%) and 2.9 (1.43% vs 0.49%) times higher, bipolar disorder was 2.5 (1.41% vs 0.57%) and 3 (1.02% vs 0.34%) times higher, depression diagnosis was 1.5 (8.47% vs 5.82%) and 3.4 (10.17% vs 2.97%) higher, trauma-related disorder was 1.5 (6.00% vs 4.10%) respectively 2.9 (4.45% vs 1.56%) times higher, anxiety disorder was 1.2 (6.88% vs 5.72%) and 2.2 (6.54% vs 2.93%) times higher than in their non-infected peers. CONCLUSION: Despite effective ART, many individuals with HIV have an impaired mental health and a history of drug abuse that may threaten the vision of a contained epidemic.

The association among smoking, HSV-1 exposure, and cognitive functioning in schizophrenia, bipolar disorder, and non-psychiatric controls.

Previous investigations have found that smokers with schizophrenia demonstrate reduced performance on cognitive tasks compared to non-smokers. However previous studies have not taken into account other environmental factors associated with cognitive functioning such as exposure to Herpes Simplex Virus type 1 (HSV-1). We examined these factors in a sample consisting of individuals with schizophrenia (n=773), bipolar disorder (n=493), or controls without a psychiatric disorders (n=548). Participants were assessed on a cognitive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and had a blood sample drawn to measure seropositivity to HSV-1. Within each group linear regression models were constructed to determine whether cigarette smoking and HSV-1 seropositivity were jointly associated with cognitive functioning after adjusting for relevant covariates. Within the schizophrenia group, the effect size of lower total cognitive score was -0.279 (p<0.0001) for individuals who were both smokers and HSV-1 seropositive and a significant effect was found in all cognitive domains. The odds of being in the highest quartile of RBANS Total score were significantly lower for smokers (OR=0.58, 95% CI 0.41, 0.82, p=0.002). Smoking was not as consistently associated with levels of cognitive functioning in the bipolar disorder or the non-psychiatric control group. While experimental studies show that nicotine transiently improves functioning on sensory gating and attention tasks known to be deficient in schizophrenia, long-term nicotine exposure via smoking appears to have an adverse effect on cognitive functioning.

Gestational influenza and risk of hypomania in young adulthood: prospective birth cohort study.

BACKGROUND: Previous studies have suggested a possible link between exposure to influenza in utero and bipolar disorder in adulthood. Using data from a prospective birth cohort, we aimed to test for an association between exposure to gestational influenza and the experience of hypomania assessed in early adulthood. METHODS: We used data on 2957 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). The two main outcomes of interest were hypomania, assessed using the Hypomania Checklist (HCL-32) at age 22-23, and 'hypomania plus previous psychotic experiences (PE)'. Maternally-reported gestational influenza was the exposure of interest. Multivariable logistic regression was used and estimates of association were adjusted for a range of possible confounding factors, including maternal smoking in pregnancy. RESULTS: Relative to controls, rates of exposure to gestational influenza were higher for participants with hypomania (24.0%) and for participants with 'hypomania plus PE' (34.2%), but univariate and multivariable analyses of an association between gestational influenza and hypomania (with and without previous PE) were not significant. LIMITATIONS: The response rate to those who were sent the HCL-32 questionnaire was 36.8%. As a result, some analyses may have been under-powered to detect a true effect. Influenza infection during pregnancy was self-reported by mothers. CONCLUSIONS: In this prospective population study, gestational influenza was not identified as a clear risk factor for lifetime hypomania or for 'hypomania with PEs' in young adult offspring. It is possible that previous reports of an association between gestational influenza and bipolar disorder in adulthood have been confounded by factors such as maternal smoking during pregnancy.

Type specific Real time PCR for detection of human herpes virus 6 in schizophrenia and bipolar patients: a case control study.

BACKGROUND: Schizophrenia (SC) and bipolar disorder (BD) are among the most devastating diseases worldwide. There are several lines of evidence suggesting that viruses may play significant roles in the etiology of these mental disorders. The aim of this study was the detection of HHV-6A/B in the peripheral blood mononuclear cells (PBMC) of SC and BD patients versus the healthy control (HC) subjects using a new method of type-specific Real time PCR analysis. METHODS: A type-specific Real time PCR was performed for simultaneous detection and typing of HHV-6A/B in the PBMCs of 120 SC and BD patients and 75 HCs. RESULTS: Only one case of HHV-6B out of 120 (0.8 %) SC and BD patients and two cases of HHV-6A (2.7 %) in 75 HCs were detected. CONCLUSIONS: The low levels of HHV-6 detection in PBMCs, severely limited the capacity of this study to investigate the association between the presence of HHV-6 and BD or SC in this population, thus no conclusions can be drawn in this regard. Meanwhile this study introduces a Real time PCR based method for type specific detection of HHV-6A/B in clinical samples.

Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States.

The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I.

Immune alterations in acute bipolar depression.

OBJECTIVE: Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression. METHOD: Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up. RESULTS: The sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers. CONCLUSION: Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania.

Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation.

Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.

HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors.

BACKGROUND: Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties. METHODS: Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection. RESULTS: Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p<0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p<0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05). CONCLUSIONS: HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.