High unrecognized SARS-CoV-2 exposure of newly admitted and hospitalized psychiatric patients.

BACKGROUND: Patients with pre-existing mental disorders are at higher risk for SARS-CoV-2 infection and adverse outcomes, and severe mental illness, including mood and psychosis spectrum disorders, is associated with increased mortality risk. Despite their increased risk profile, patients with severe mental illness have been understudied during the pandemic, with limited estimates of exposure in inpatient settings. OBJECTIVE: The aim of this study was to describe the SARS-CoV-2 seroprevalence and antibody titers, and pro-inflammatory cytokine concentrations of newly admitted or hospitalized psychiatric inpatients without known history of COVID-19 infection, using robust quantitative multi-antigen assessments, and compare patients' exposure to that of hospital staff. METHODS: This multi-centric, cross-sectional study compared SARS-CoV-2 seroprevalence and titers of 285 patients (University Psychiatric Centre Duffel [UPCD] N = 194; Assistance-Publique-Hopitaux de Paris [AP-HP] N = 91), and 192 hospital caregivers (UPCD N = 130; AP-HP N = 62) at two large psychiatric care facilities between January 1st and the May 30th 2021. Serum levels of SARS-CoV-2 antibodies against Spike proteins (full length), spike subunit 1 (S1), spike subunit 2 (S2), spike subunit 1 receptor binding domain (S1-RBD) and Nucleocapsid proteins were quantitatively determined using an advanced capillary Western Blot technique. To assess the robustness of the between-group seroprevalence differences, we performed sensitivity analyses with stringent cut-offs for seropositivity. We also assessed peripheral concentrations of IL-6, IL-8 and TNF-a using ELLA assays. Secondary analyses included comparisons of SARS-CoV-2 seroprevalence and titers between patient diagnostic subgroups, and between newly admitted (hospitalization ≤ 7 days) and hospitalized patients (hospitalization > 7 days) and correlations between serological and cytokines. RESULTS: Patients had a significantly higher SARS-CoV-2 seroprevalence (67.85 % [95% CI 62.20-73.02]) than hospital caregivers (27.08% [95% CI 21.29-33.77]), and had significantly higher global SARS-CoV-2 titers (F = 29.40, df = 2, p < 0.0001). Moreover, patients had a 2.51-fold (95% CI 1.95-3.20) higher SARS-CoV-2 exposure risk compared to hospital caregivers (Fisher's exact test, P < 0.0001). No difference was found in SARS-CoV-2 seroprevalence and titers between patient subgroups. Patients could be differentiated most accurately from hospital caregivers by their higher Spike protein titers (OR 136.54 [95% CI 43.08-481.98], P < 0.0001), lower S1 (OR 0.06 [95% CI 0.02-0.15], P < 0.0001) titers and higher IL-6 (OR 3.41 [95% CI 1.73-7.24], P < 0.0001) and TNF-α (OR 34.29 [95% CI 5.00-258.87], P < 0.0001) and lower titers of IL-8 (OR 0.13 [95% CI 0.05-0.30], P < 0.0001). Seropositive patients had significantly higher SARS-COV-2 antibody titers compared to seropositive hospital caregivers (F = 19.53, df = 2, P < 0.0001), while titers were not different in seronegative individuals. Pro-inflammatory cytokine concentrations were not associated with serological status. CONCLUSION: Our work demonstrated a very high unrecognized exposure to SARS-CoV-2 among newly admitted and hospitalized psychiatric inpatients, which is cause for concern in the context of highly robust evidence of adverse outcomes following COVID-19 in psychiatric patients. Attention should be directed toward monitoring and mitigating exposure to infectious agents within psychiatric hospitals.

Human Endogenous Retroviruses and Type 1 Diabetes.

PURPOSE OF THE REVIEW: The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression. RECENT FINDINGS: The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells. The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.

Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis.

Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.

Development of a pan-retrovirus detection system for multiple sclerosis studies.

INTRODUCTION: Although recent claims implicating HTLV-1 in multiple sclerosis (MS) have been refuted, several reports suggest that another, hitherto uncharacterised, retrovirus may be involved. We have developed and applied a novel PCR-based strategy to explore this possibility. METHODS: Degenerate oligonucleotides were used in a semi-nested format to amplify, from reverse-transcribed RNA, a region of the pol gene which is well conserved amongst all known retroviruses. RESULTS: The 'pan-retrovirus' detection system was shown to be capable of detecting diverse retroviruses including human lentivirus, human oncovirus, simian D-type virus and murine oncovirus. The 'pan-retrovirus' technique identified a novel retroviral sequence, designated MSRV-cpol, in the serum of an MS patient and also in purified virions from MS patient-derived tissue cultures. Sequence comparisons suggest that in the pol gene MSRV is related (approximately 75% homology) to the endogenous retroviral element ERV9. CONCLUSION: These findings lend further support to the concept of retroviral involvement in MS.

Expression of endogenous retroviruses in blood mononuclear cells and brain tissue from multiple sclerosis patients.

OBJECTIVES: To compare the expression of endogenous retroviruses in MS patients and controls. MATERIAL AND METHODS: Peripheral blood mononuclear cells were obtained from 22 MS patients, a corresponding number of matched healthy donors and five patients with other central nervous system disease. Also brain specimens from MS patients and controls were obtained. Transcripts of various endogenous retroviruses in these samples were detected by RNA-PCR. RESULTS: Several endogenous retroviral sequences were transcribed in peripheral blood mononuclear cells and brain tissue from MS patients as well as controls. A composite transcript of an endogenous retrovirus and a zinc finger sequence was more frequently found in healthy donors than in MS patients. CONCLUSION: Some endogenous retroviruses are normally transcribed in white blood cells and brain tissue. The significance of those findings, which concerned the composite transcripts of the zinc finger sequence and its associated endogenous retrovirus is uncertain.

Cell cultures and associated retroviruses in multiple sclerosis. Collaborative Research Group on MS.

Retroviral particles associated with reverse transcriptase (RT) activity in cell-cultures from MS patients have been reported by different groups. Cell-cultures have been used for the study and characterization of the corresponding retroviral genome which we have shown is related to ERV9 in the pol region. Previously unpublished details of a study with monocyte cultures are presented together with observations on leptomeningeal and choroid-plexus cultures. The generation of self-transformed cultures after inhibition of interferon, followed by the loss of retroviral expression and recurrent apoptosis, is analyzed. Retroviral particles with RT-activity are produced in monocyte cultures with an apparent correlation with MS disease activity. However, though leptomeningeal and choroid plexus cells from MS can be passaged for a limited period, their evolution in vitro is not compatible with stable retroviral expression. These culture limitations greatly hampered progress on the elucidation of the retroviral genome sequence.

Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis.

In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.

Human retroviral sequences associated with extracellular particles in autoimmune diseases: epiphenomenon or possible role in aetiopathogenesis?

Publications describing retroviral sequences associated with extracellular particles in Sjögren's syndrome or systemic lupus erythematosus, multiple sclerosis, and type I diabetes present novel arguments and raise complex questions about eventual relationships between retroviruses and autoimmunity. They are presented and discussed in the present review, preceded by an overview of the biology of retroviral elements.

Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates.

A novel human endogenous retrovirus, HERV-W, has been characterized on the basis of multiple sclerosis-associated retrovirus (MSRV) probes. We have analyzed the phylogenetic distribution of HERV-W in humans and other primate species. As HERV-W presents a C/D chimeric nature and is largely composed of deleted elements, Southern blots were performed using gag, pol, env, and LTR probes. The relative complexities observed for gag, pol, env, and LTR regions were similar in humans, apes, and Old World monkeys, the minimal number of bands observed after Southern blot analysis being 25, 50, 10, and at least 100, respectively. The HERV-W family entered the genome of catarrhines more than 25 million years ago.

Detection of a gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients.

We recently showed that peripheral blood cell supernatants from multiple sclerosis (MS) patients, containing reverse transcriptase activity and retroviral RNA from the newly human identified multiple sclerosis retrovirus (MSRV), also secrete a cytotoxin which induces death of primary mouse cortical glial cells. We have hypothesized that macrophages could release this cytotoxin in the cerebrospinal fluid. The cerebrospinal fluid cytotoxicity from 166 patients with various neurological diseases (including MS patients) was tested on glial cells in vitro. Our bioassay shows that a glial cytotoxic activity is significantly present in cerebrospinal fluid from patients with relapsing-remitting MS at relapse. Since this cytotoxic activity seems to correlate with active cases of MS, it may represent a critical pathogenic factor in the neuropathology of MS.

Sporadic ALS/MND: a global neurodegeneration with retroviral involvement?

Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out.

A gliotoxic factor and multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) is unknown. Searching for possible toxic factors, it was found that 3-day exposure to heat-treated cerebrospinal fluid (CSF) from MS patients caused apoptotic death of astrocytes and oligodendrocytes, but not fibroblasts, myoblasts, Schwann cells, endothelial cells and neurons, in vitro. CSFs from other inflammatory or non-inflammatory neurological diseases showed no toxicity. Exposure of these glial cells to partially purified MS CSF produced DNA fragmentation, apoptotic bodies, chromatin condensation, cell shrinkage, and changes in the levels of known cytokines. A cytotoxic factor, called gliotoxin, was characterized chromatographically as a stable 17-kDa glycoprotein. Since this protein is highly cytotoxic for astrocytes and oligodendrocytes, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, such as blood-brain barrier involvement and demyelination.

[MSRV retrovirus and gliotoxin protein: potential biological markers in multiple sclerosis?]. / Rétrovirus MSRV et protéine gliotoxique: marqueurs biologiques potentiels dans la sclérose en plaques?

The aetiopathogeny of multiple sclerosis, a neurological disease which prevalence and duration generate an important problem of public health in industrialized countries where it is most frequent, is not clearly understood. The keys for the diagnosis and therapeutic strategies of MS are nonetheless dependent upon the identification of a well-defined aetiology and upon the understanding of the mechanisms and pathogenic connexions which lead to the demyelinating lesions of the central nervous system and to the dysfunctions of the immune system (autoimmunity) characteristic for the disease. The recent identification of a retroviral agent (MSRV) which produces extracellular particles detectable in the plasma, the CSF, and in some cell cultures from patients with MS, as well as of a cytotoxic factor targeting glial cells (gliotoxin) detected in parallel, could help elucidating the aetiopathogeny of MS. The usefulness of biological markers and targets derived from MSRV retrovirus and this gliotoxin, in the diagnostic and therapeutic perspectives for MS, is discussed in the light of the different aetiopathogenic hypotheses for the disease. From our results it is conceivable that a retroviral agent and pathogenic molecules such as this gliotoxin and an eventual MSRV-associated retroviral superantigen might initiate and perpetuate the cascade of events leading to MS. However, similar data on different simple retroviruses were recently published concerning autoimmune diseases such as diabetes type 1, Sjögren's syndrome and systemic lupus erythematosis, which could prefigurate a broader concept for the role of such retroviruses in the aetiopathogenesis of autoimmune diseases.

[Present status of retroviruses in human infectious disease]. / Actualité des rétrovirus en pathologie infectieuse humaine.

Retroviruses have been shown to be oncogenic in many animals for decades. In humans, retroviruses became worth of interest no sooner than in the early eighties. HIV is at the moment the last one of the well studied human retroviruses. Besides, HTLV-1, the prevalence of which is geographically restricted, is associated with adult T-cell leukemia/lymphoma, and with chronic myelopathies. This virus, as well as the closely related and rarer HTLV-2, is transmitted sexually, probably perinatally, and by infected blood and blood products. Among spumaviruses, an additional retrovirus subfamily, the human spumaretrovirus (HSRV)--or human foamy virus--seems to have a low pathogenicity for human, although it is believed to be associated with Graves disease. Finally, endogenous retroviruses address new issues in humans, in particular with regard to relationship between virus and host genetic inheritance. These viruses could play a role in neurodegenerative or autoimmune diseases.

Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.

Multiple sclerosis-associated retroviral agent (MSRV)-stimulated cytokine production in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Human endogenous retroviruses are suggested to play a pathogenic role in multiple sclerosis (MS); one of such retroviruses, the MS-associated retroviral agent (MSRV) has repeatedly been isolated in MS patients. OBJECTIVE AND METHODS: We analyzed cytokine profiles in MSRV envelope protein (MSRV ENV-SU)-stimulated peripheral blood mononuclear cells of 30 relapsing-remitting MS patients with either acute (AMS) (n = 13) or stable (SMS) (n = 17) disease. Results suggest that MSRV ENV-SU induces the production of inflammatory cytokines, including tumor necrosis factor-alpha (P < 0.05) and interferon-gamma (P < 0.004) in AMS patients and of interleukin-10 (P < 0.05), an inflammation-dampening cytokine, in SMS individuals. CONCLUSIONS: These data strengthen the hypothesis indicating that MSRV could be involved in the pathogenesis of MS.

Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression.

The human endogenous retrovirus (HERV)-W multicopy family was identified in human DNA from the previously characterized multiple sclerosis associated retroviral element (MSRV). Upregulation of the HERV-W POL has been reported in cerebrospinal fluid of patients with schizophrenia. The expression of capsid (GAG) protein of HERV-W was studied by immunohistochemistry and western blotting in postmortem brain tissue of the anterior cingulate cortex and hippocampal formation of normal controls and of patients with schizophrenia, bipolar disorder and major depression. A physiological expression of GAG protein was detected in neurons as well as astroglial cells in normal brain both in the anterior cingulate cortex and in the hippocampal formation. There was a statistically significant reduction of this expression in neurons and astroglial cells in brains from individuals with schizophrenia, major depression, and bipolar disorder. The results from the present study confirm that GAG protein encoded by the HERV-W multicopy gene family is expressed in cells of the central nervous system under normal conditions. Our findings of a cell type-, brain region- and disease-specific reduced expression in schizophrenia, major depression, and bipolar disorder are compatible with a pathophysiological role of HERVs in human brain disorders. The causes and biological consequences of this differential regulation will be the subject of further investigations.

Correlation analysis between bovine populations, other farm animals, house pets, and multiple sclerosis prevalence.

In a previous study we analyzed the possible relationship between dairy product consumption and multiple sclerosis (MS) worldwide. We showed that a good correlation (Spearman rank p = 0.836), statistically strongly significant (p < 0.0001), existed between liquid cow milk consumption and MS prevalence. The interpretation of this strong correlation between MS and milk consumption is still unclear: fresh milk could be considered as a cofactor, but it could also reflect a much stronger association with MS of another unstudied factor, well correlated with milk consumption (yet, this is not the case for latitude). Obviously, the bovine population in each country and, particularly milk cows, has to be considered. In the present study, we analyze the correlations existing between the figures of national cow milk production and MS prevalence in 20 countries. We also analyze the correlations with the whole bovine, ovine, caprine, porcine, horse, poultry, cat and dog populations. Here again we find significant correlations between (i) cow milk production per inhabitant, (ii) national bovine density per inhabitant, and (iii) local bovine geographic density, and MS prevalence. However, these correlations are relatively weaker than that found with fresh liquid milk consumption in our previous study. No correlation is found with other farm animals or with pets in the same countries. The epidemiological significance of these results, suggesting a preponderant role of fresh cow milk, is discussed.

Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study.

Multiple sclerosis (MS) epidemiology suggests that different factors are involved in the clinical expression of the disease. Alimentary cofactors have already been considered, but mainly theoretically. We have studied the relationship between MS prevalence and dairy product consumption in 27 countries and 29 populations all over the world, with Spearman's correlation test. A good correlation between liquid cow milk and MS prevalence (rho = 0.836) was found; this correlation was highly significant (p < 0.001). A low but still significant correlation was obtained with cream or butter consumption (rho = 0.619 and rho = 0.504, respectively). No correlation was found for cheese. These results suggest that liquid cow milk could contain factor(s) - no longer present in the processed milk - influencing the clinical appearance of MS. The possible role of some dairy by-products is discussed in the light of a multifactorial etiology of MS.