Neurotropic Infectious Agents Research Articles

Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia

Cognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment.

The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small?

The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.

Suicide attempts and markers of immune response in individuals with serious mental illness

Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.

Connections Between Herpes Simplex Virus Type 1 and Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is currently one of the most studied neurodegenerative disorders in humans. First reported in 1907, the disease has a familial form which represents approximately 5% of cases, while the remaining, sporadic cases are of multifactorial etiology. The disease progression of the latter form has specific pathological and functional characteristics, which have unknown etiology. Several authors have proposed a viral etiology for AD, while others implicate many neurotropic infectious agents. This review compares research findings regarding pathways and effects of neuropathological viruses with the pathways and effects involved in the progression of AD. The similarities are striking and provide a compelling argument for a pathogen-based etiology of AD.

Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort.

Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain. In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders. The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection. Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age-related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment.

An observational study of inflammation in the central nervous system in patients with bipolar disorder.

The potential influence of infections and immunological changes on the aetiology and pathogenesis of bipolar disorder (BD) has been discussed. Our aim was to detect intrathecal specific antibody synthesis against the neurotropic infectious agents that have previously been linked to BD. Paired cerebrospinal fluid (CSF) and serum samples from 40 patients with BD were analysed using the enzyme-linked immunosorbent assay to detect the concentration of antibodies against the following neurotropic infectious pathogens: Toxoplasma gondii (T.gondii), herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The specific antibody index (AI) was calculated, and an AI>1.4 was considered to be evidence of intrathecal specific antibody synthesis. Twenty-six patients with pseudotumour cerebri served as controls. Eight out of 40 patients with BD displayed specific intrathecal antibody synthesis against at least one of the tested neurotropic agents compared to only one patient in the control group (p=0.061, not significant). Of these eight patients with BD, no significant prevalence of any particular neurotropic pathogen was evident. Five out of 40 patients with BD showed oligoclonal bands in the CSF, suggestive of a chronic immune reaction in the central nervous system (CNS). We found evidence for increased production of antibody in the CSF of individuals with BD. However, the trend for polyspecific intrathecal antibody synthesis, as well as the presence of oligoclonal bands, might indicate activation of the intrathecal humoral immune system in a subgroup of patients with BD, as it is known to be associated with autoimmune disorders of the CNS.

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

IntroductionMultiple studies have documented immune activation in many individuals with schizophrenia suggesting that antigens capable of generating a prolonged immune response may be important environmental factors in many cases of this disorder. While existing studies have found single-agent associations of antibodies to food and neurotropic infectious agents with schizophrenia, a simultaneous examination of multiple agents may shed light on agent interactions or possible etiopathogenic pathways. MethodsWe used traditional regression and novel statistical techniques to examine associations of single and combined infectious and food antigens with schizophrenia. We tested 6106 serum samples from 855 cases and 1165 matched controls. ResultsHigher antibody levels to casein were borderline significant in the prediction of schizophrenia (HR=1.08, p=0.06). Study participants with higher cytomegalovirus (CMV) IgG antibody levels had a reduced risk of developing schizophrenia (HR=0.90; p=0.02). While IgG antibodies to gliadin, Toxoplasma gondii, vaccinia, measles, and human herpesvirus-6 (HHV-6) showed no significant independent associations with schizophrenia, the increase in antibody levels to several combinations of agents, to include casein, measles, CMV, T. gondii and vaccinia, was predictive of an 18–34% increase in the risk of developing schizophrenia. ConclusionCertain patterns of antibodies, involving some agents, were predictive of developing schizophrenia, with the magnitude of association rising when the level of antibodies increased to two or more agents. A heightened antibody response to a combination of several infectious/food antigens might be an indicator of an altered immune response to antigenic stimuli.

A bipolar disorder patient becoming asymptomatic after adjunctive anti-filiarasis treatment: a case report

BackgroundEvidence suggests that neurotropic infectious agents might be involved in bipolar disorder. So far, few have been written for the association between parasitic infection and bipolar disorder. Filariasis is a parasitic disease acting ruthlessly via mosquitos and affecting more than 120 million people worldwide. We present here, to our knowledge, the first description of a filariasis infected manic bipolar disorder patient fully improved in terms of psychiatric symptoms by anti-heminthic treatment.Case presentationThe patient is a 31 years-old man native of Congo. At inclusion, he presented a severe manic episode with dangerous behaviour unresolved by classic treatments. A diagnosis of filariasis bancrofti infection was made after the discovery of a systemic hypereosinophilia. Therefore, a bi-therapy of anthelmintics was conducted allowing a successful improvement with clear reduction of agitation and aggressive behaviours that could not be attributed to a modification of psychotropic treatments or filarial encephalopathy or acute disseminated encephalomyelitis.ConclusionThe ineffectiveness of psychotropic treatment of a manic episode requires the evaluation of co-morbid medical conditions such as infections which can interfere with adequate mood stabilizing medication. Filariasis by inducing chronic inflammation and immunopathologic reactions seems to play a major role in infected affective disorders patients by changing levels of cytokines of the Th1 system or indirectly damaging the brain tissue. The beneficial combination of antihelmintics and mood stabilizers, in this case, could be explained by the potential of such association to downregulate neuroinflammation and excitotoxicity processes.Altogether, these data pinpoint the requirement to explore the parasitic infectious status in case of bipolar disorder patients resistant to classic treatments and originating or living in endemic geographical areas.

Progenitor-derived Oligodendrocyte Culture System from Human Fetal Brain

Differentiation of human neural progenitors into neuronal and glial cell types offers a model to study and compare molecular regulation of neural cell lineage development. In vitro expansion of neural progenitors from fetal CNS tissue has been well characterized. Despite the identification and isolation of glial progenitors from adult human sub-cortical white matter and development of various culture conditions to direct differentiation of fetal neural progenitors into myelin producing oligodendrocytes, acquiring sufficient human oligodendrocytes for in vitro experimentation remains difficult. Differentiation of galactocerebroside+ (GalC) and O4+ oligodendrocyte precursor or progenitor cells (OPC) from neural precursor cells has been reported using second trimester fetal brain. However, these cells do not proliferate in the absence of support cells including astrocytes and neurons, and are lost quickly over time in culture. The need remains for a culture system to produce cells of the oligodendrocyte lineage suitable for in vitro experimentation. Culture of primary human oligodendrocytes could, for example, be a useful model to study the pathogenesis of neurotropic infectious agents like the human polyomavirus, JCV, that in vivo infects those cells. These cultured cells could also provide models of other demyelinating diseases of the central nervous system (CNS). Primary, human fetal brain-derived, multipotential neural progenitor cells proliferate in vitro while maintaining the capacity to differentiate into neurons (progenitor-derived neurons, PDN) and astrocytes (progenitor-derived astrocytes, PDA) This study shows that neural progenitors can be induced to differentiate through many of the stages of oligodendrocytic lineage development (progenitor-derived oligodendrocytes, PDO). We culture neural progenitor cells in DMEM-F12 serum-free media supplemented with basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF-AA), Sonic hedgehog (Shh), neurotrophic factor 3 (NT-3), N-2 and triiodothyronine (T3). The cultured cells are passaged at 2.5e6 cells per 75cm flasks approximately every seven days. Using these conditions, the majority of the cells in culture maintain a morphology characterized by few processes and express markers of pre-oligodendrocyte cells, such as A2B5 and O-4. When we remove the four growth factors (GF) (bFGF, PDGF-AA, Shh, NT-3) and add conditioned media from PDN, the cells start to acquire more processes and express markers specific of oligodendrocyte differentiation, such as GalC and myelin basic protein (MBP). We performed phenotypic characterization using multicolor flow cytometry to identify unique markers of oligodendrocyte.

Progenitor-derived Oligodendrocyte Culture System from Human Fetal Brain

Differentiation of human neural progenitors into neuronal and glial cell types offers a model to study and compare molecular regulation of neural cell lineage development. In vitro expansion of neural progenitors from fetal CNS tissue has been well characterized. Despite the identification and isolation of glial progenitors from adult human sub-cortical white matter and development of various culture conditions to direct differentiation of fetal neural progenitors into myelin producing oligodendrocytes, acquiring sufficient human oligodendrocytes for in vitro experimentation remains difficult. Differentiation of galactocerebroside(+) (GalC) and O4(+) oligodendrocyte precursor or progenitor cells (OPC) from neural precursor cells has been reported using second trimester fetal brain. However, these cells do not proliferate in the absence of support cells including astrocytes and neurons, and are lost quickly over time in culture. The need remains for a culture system to produce cells of the oligodendrocyte lineage suitable for in vitro experimentation. Culture of primary human oligodendrocytes could, for example, be a useful model to study the pathogenesis of neurotropic infectious agents like the human polyomavirus, JCV, that in vivo infects those cells. These cultured cells could also provide models of other demyelinating diseases of the central nervous system (CNS). Primary, human fetal brain-derived, multipotential neural progenitor cells proliferate in vitro while maintaining the capacity to differentiate into neurons (progenitor-derived neurons, PDN) and astrocytes (progenitor-derived astrocytes, PDA) This study shows that neural progenitors can be induced to differentiate through many of the stages of oligodendrocytic lineage development (progenitor-derived oligodendrocytes, PDO). We culture neural progenitor cells in DMEM-F12 serum-free media supplemented with basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF-AA), Sonic hedgehog (Shh), neurotrophic factor 3 (NT-3), N-2 and triiodothyronine (T3). The cultured cells are passaged at 2.5e6 cells per 75cm flasks approximately every seven days. Using these conditions, the majority of the cells in culture maintain a morphology characterized by few processes and express markers of pre-oligodendrocyte cells, such as A2B5 and O-4. When we remove the four growth factors (GF) (bFGF, PDGF-AA, Shh, NT-3) and add conditioned media from PDN, the cells start to acquire more processes and express markers specific of oligodendrocyte differentiation, such as GalC and myelin basic protein (MBP). We performed phenotypic characterization using multicolor flow cytometry to identify unique markers of oligodendrocyte.

Neurotropic Infectious Agents and Cognitive Impairment in Schizophrenia

The links between infectious agents and risk for schizophrenia have been widely debated, but few investigations have focused on "epidiagnostic" effects, eg, whether exposures to infectious agents alter key clinical aspects of the disorder, such as cognitive impairment. The present theme issue evaluates epidiagnostic cognitive effects of two common infectious agents, namely Herpes Simplex Virus, type 1 and Toxoplasma gondii.

Acute hydrocephalus due to impaired CSF resorption in Toscana virus meningoencephalitis

Toscana virus, a neurotropic infectious agent endemic to Mediterranean countries, classified in the sandfly fever virus group (genus Phlebovirus, family Bunyaviridae), is a frequent cause of aseptic meningitis and encephalitis in Italy.1 The disease usually has a favorable outcome, and reports of severe courses are rare.1,2 We present an unusual case of acute hydrocephalus as the initial symptom of Toscana virus meningoencephalitis. ### Case report. A 21-year-old student presented with a 36-hour history of progressive bifronto-temporal headaches, retroorbital pressure, fever, nausea, vomiting, and double vision due to bilateral sixth cranial nerve deficits. Eight days before presentation, he had returned from a 2-week camping trip to Umbria, Italy, where he had suffered multiple tick bites. The patient's past personal and travel history was otherwise unremarkable. Apart from bilateral abductor nerve deficits, neurologic examination was normal, in particular showing no signs …

Structural abnormalities in the cuneus associated with Herpes Simplex Virus (type 1) infection in people at ultra high risk of developing psychosis

It has been suggested that some cases of schizophrenia may be caused by an interaction between physiological risk factors and exposure to certain neurotropic infectious agents such as Herpes Simplex Virus type 1 (HSV1). This study investigated whether HSV1 exposure was associated with structural brain abnormalities in individuals who, because of genetic or other factors, were deemed at ultra high risk (UHR) of developing psychosis. Twenty-five UHR individuals with a history of HSV1 exposure (HSV1+), 33 UHR participants without a history of HSV1 exposure (HSV1−) and 19 healthy controls participated in the study. All participants underwent a T1-weighted structural MRI scan, and HSV1 exposure was determined based on the presence of IgG class antibodies in the blood serum. Voxel based morphometry revealed that the HSV1+ participants exhibited volumetric gray matter reductions in the cuneus, relative to both the HSV1− and healthy control participants (p<0.05, small volume corrected for familywise error). The results of the study suggest that a history of HSV1 infection is associated with volumetric gray matter reductions in individuals at ultra-high risk for developing psychosis, and are consistent with previous studies that have identified structural gray matter abnormalities in HSV1-infected patients with established schizophrenia.

Evidence for Viral Etiology of Multiple Sclerosis

The etiology of multiple sclerosis (MS) is unknown, and several hypotheses have been advanced over the past century to explain it. Despite much effort, no single cause has been established. One of the most appealing hypotheses is that of infection due to a neurotropic infectious agent, possibly a virus. There are several lines of data to support this hypothesis. First, there are clear examples of inflammatory demyelinating disease caused directly or indirectly by viral infections in both humans and animals. Second, there is a strong environmental component to multiple sclerosis. Finally, there is aberrant immune reactivity against various viruses. Recent candidates have included measles and the related canine distemper virus, human herpesvirus 6, human endogenous retroviruses, and Epstein-Barr virus. The evidence is most extensive for the latter and will be discussed in some detail.

Serological evidence of exposure to Herpes Simplex Virus type 1 is associated with cognitive deficits in the CATIE schizophrenia sample

Cognitive impairment is a core feature of schizophrenia. Previous studies have indicated that exposure to neurotropic infectious agents such as Herpes Simplex Virus type 1 may contribute to cognitive deficits and neuroanatomical abnormalities in individuals with schizophrenia. We examined the association between exposure to neurotropic infectious agents and cognitive function in 1308 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. This sample included all of the individuals in the CATIE trial for whom baseline blood samples were available. Cognition was evaluated at baseline by a test battery which yielded composite scores in the domains of processing speed, verbal memory, vigilance, reasoning, and working memory as well as a summary neurocognitive score. Solid phase immunoassay techniques were used to measure IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Cytomegalovirus (CMV), and to Toxoplasma gondii ( T gondii) in the sera of the study individuals. We found a significant association between the neurocognitive summary score and antibodies to HSV-1 but not to HSV-2, CMV, or T. gondii. There was also a significant association between HSV-1 exposure and the Verbal Memory, Vigilance, and Processing Speed composite scores. HSV-1 may modulate the neurocognitive function of individuals with schizophrenia through its ability to establish latency in the central nervous system and undergo periodic reactivation. A better understanding of the role of HSV-1 may lead to better methods of treatment for the cognitive impairments associated with schizophrenia.

Borna disease virus: molecular analysis of a neurotropic infectious agent

Borna disease virus: molecular analysis of a neurotropic infectious agent