Herpesvirus may lead to bipolar, depression

An international team of scientists led by Bhupesh Prusty — from the
Department of Microbiology at the University of Würzburg in Germany —
discovered that in the brains of people who lived with bipolar and major
depression, a class of neurons called Purkinje cells was infected with
the herpesvirus HHV-6A.
Purkinje neurons are inhibitory brain cells located in the human cerebellum, which is
the brain area responsible for controlling movement, muscles, balance,
and posture.
However, some research has also tied this brain region to language, cognition, and mood.

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders Frontiers in microbiology

Herpes Viruses Implicated in Alzheimer’s Disease

The brains of Alzheimer’s disease patients have an abnormal build up of amyloid-β proteins and tau tangles, which, according to many researchers, drives the ultimately fatal cognitive disease. This theory is being amended to a newer one, which posits that microbes may trigger Alzheimer’s pathology. Two new studies, using different approaches, further bolster this pathogen theory. Analyzing the transcriptomes of post-mortem brain samples from patients with Alzheimer’s disease, one group of researchers finds that two strains of human herpes virus (Roseoloviruses HHV-6 and HHV-7) are significantly more abundant than in the brains of people of the same age without Alzheimer’s disease. Gene networks in the brains of Alzheimer’s patients with these strains are also rewired such that disease-related genes are differentially expressed compared to controls.

In the other study, another team of investigators observed in mouse models and in a three-dimensional human neuronal cell culture that a Herpesviridae infection could seed amyloid-β plaques.

Persistent Herpesvirus Infections and Telomere Attrition Over 3 Years in the Whitehall II Cohort | The Journal of Infectious Diseases | Oxford Academic

Telomere (Photo credit: Wikipedia)

 The determinants of telomere attrition, a potential marker of cellular aging, are not well understood. Persistent herpesvirus infections including cytomegalovirus (CMV) infection may be particularly important for telomere dynamics via mechanisms such as inflammation, oxidative stress, and their impact on peripheral blood lymphocyte composition. This study examined the association of 4 human herpesviruses (CMV, herpes simplex virus type 1, human herpesvirus type 6, and Epstein-Barr virus) with change in leukocyte telomere length (LTL) over 3 years in 400 healthy individuals (aged 53–76 years) from the Whitehall II cohort. CMV, herpes simplex virus type 1, and human herpesvirus 6 infection were independently associated with greater 3-year LTL attrition, with no association found for Epstein-Barr virus. The magnitudes of these associations were large, for example, the equivalent of almost 12 years of chronological age for those CMV seropositive. Seropositivity to more herpesviruses was additively associated with greater LTL attrition (3 herpesviruses vs none, β = −0.07 and P = .02; 4 infections vs none, β = −0.14 and P < .001). Higher immunoglobulin G antibody levels among those seropositive to CMV were also associated with shorter LTL at follow-up. These associations were robust to adjustment for age, sex, employment grade, body mass index, and smoking status. These results suggest that exposure to infectious agents should be an important consideration in future studies of telomere dynamics."



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Hidden herpes virus may play key role in MS, other brain disorders -- ScienceDaily

 "The ubiquitous human herpesvirus 6 (HHV-6) may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. The findings, which appear in the journal Scientific Reports, may help explain the differences in severity in symptoms that many people with the disease experience.

"While latent HHV-6 -- which can be found in cells throughout the brain -- has been associated with demyelinating disorders like multiple sclerosis it has not been clear what role, if any, it plays in these diseases," said Margot Mayer-Proschel, Ph.D., an associate professor at the University of Rochester Medical Center Department of Biomedical Genetics and co-author of the study. "These findings show that, while in the process of hiding from the immune system, the virus produces a protein that has the potential to impair the normal ability of cells in the brain to repair damaged myelin.""



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Autism risk linked to herpes infection during pregnancy

Women actively infected with genital herpes ( HSV-2) during early pregnancy had twice the odds of giving birth to a child later diagnosed with autism spectrum disorder (ASD), according to a study by scientists at the Center for Infection and Immunity at Columbia University's Mailman School of Public Health and the Norwegian Institute of Public Health."



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Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection | Particle and Fibre Toxicology | Full Text

Background

Inhalation of environmental (nano) particles (NP) as well as persistent herpesvirus-infection are potentially associated with chronic lung disease and as both are omnipresent in human society a coincidence of these two factors is highly likely. We hypothesized that NP-exposure of persistently herpesvirus-infected cells as a second hit might disrupt immune control of viral latency, provoke reactivation of latent virus and eventually lead to an inflammatory response and tissue damage.

Results

To test this hypothesis, we applied different NP to cells or mice latently infected with murine gammaherpesvirus 68 (MHV-68) which provides a small animal model for the study of gammaherpesvirus-pathogenesis in vitro and in vivo. In vitro, NP-exposure induced expression of the typically lytic viral gene ORF50 and production of lytic virus. In vivo, lytic viral proteins in the lung increased after intratracheal instillation with NP and elevated expression of the viral gene ORF50 could be detected in cells from bronchoalveolar lavage. Gene expression and metabolome analysis of whole lung tissue revealed patterns with striking similarities to acute infection. Likewise, NP-exposure of human cells latently infected with Epstein-Barr-Virus also induced virus production.

Conclusions

Our results indicate that NP-exposure of persistently herpesvirus-infected cells – murine or human – restores molecular signatures found in acute virus infection, boosts production of lytic viral proteins, and induces an inflammatory response in the lung – a combination which might finally result in tissue damage and pathological alterations.

Mitochondrial DNA stress primes the antiviral innate immune response : Nature : Nature Publishing Group

 "Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity."



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Activation of Human Herpesvirus Replication by Apoptosis.

 A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g. butyrate) were thought to end latency. We recently showed that Kaposi's Sarcoma-associated Herpesvirus (KSHV, or Human herpesvirus-8, HHV-8) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the RTA transcriptional activator, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology we studied cell lines latently infected with Epstein-Barr Virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, suggesting that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance.

Scientists Identify Unknown Proteins Of The Herpesvirus

The genome encodes the complete information needed by an organism, including that required for protein production. Viruses, which are up to a thousand times smaller than human cells, have considerably smaller genomes. Using a type of herpesvirus as a model system, the scientists of the Max Planck Institute of Biochemistry in Martinsried near Munich and their collaboration partners at the University of California in San Francisco have shown that the genome of this virus contains much more information than previously assumed. The researchers identified several hundred novel proteins, many of which were surprisingly small. 

Imbalanced Oxidative Stress Causes Chlamydial Persistence during Non-Productive Human Herpes Virus Co-Infection.

Both human herpes viruses and Chlamydia are highly prevalent in the human population and are detected together in different human disorders. Here, we demonstrate that co-infection with human herpes virus 6 (HHV6) interferes with the developmental cycle of C. trachomatis and induces persistence. Induction of chlamydial persistence by HHV6 is independent of productive virus infection, but requires the interaction and uptake of the virus by the host cell. On the other hand, viral uptake is strongly promoted under co-infection conditions. Host cell glutathione reductase activity was suppressed by HHV6 causing NADPH accumulation, decreased formation of reduced glutathione and increased oxidative stress. Prevention of oxidative stress restored infectivity of Chlamydia after HHV6-induced persistence. We show that co-infection with Herpes simplex virus 1 or human Cytomegalovirus also induces chlamydial persistence by a similar mechanism suggesting that Chlamydia -human herpes virus co-infections are evolutionary shaped interactions with a thus far unrecognized broad significance.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens.

RESULTS:

PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status.

CONCLUSIONS:

Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Compound discovered that boosts effect of vaccines against HIV and flu

Oxford University scientists have discovered an adjuvant polymer (polyethyleneimine) that boosts the effect of vaccines against viruses like flu, HIV and herpes in mice.

Childhood virus infection linked to prolonged seizures with fever

New research shows that human herpesviruses (HHV)-6B and HHV-7, commonly know as roseola virus), account for one third of febrile status epilepticus (FSE) cases. Results of the FEBSTAT prospective study now available in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy (ILAE), suggest that HHV-6B may be involved in the development of epilepsy and further research is urgently needed.

How the human body controls viruses thought to cause a variety of cancers

New research from the Trudeau Institute addresses how the human body controls gamma-herpesviruses, a class of viruses thought to cause a variety of cancers. The study, carried out in the laboratory of Dr. Marcia Blackman, awaits publication in The Journal of Immunology. Led by postdoctoral fellow Mike Freeman, with assistance from other laboratory colleagues, the study describes the role of white blood cells in controlling gamma-herpesvirus infections and has implications for the treatment and prevention of certain cancers.

Children with asthma at higher risk for shingles: study

Children with asthma have a higher risk for developing shingles -- a painful skin rash -- following infection with the herpes zoster virus, new research reveals.

Human herpesvirus 6 and 7 reactivation and disease activity in multiple sclerosis.

Recent studies have focused on the associations between human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), and multiple sclerosis (MS). The aim of this study was to investigate the associations between HHV-6 and HHV-7 reactivation and MS disease activity, and interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) production.

MATERIAL AND METHODS:

The frequency of plasma viremia by nested polymerase chain reaction and transcription of viral mRNA in peripheral blood mononuclear cells by reverse transcriptase-polymerase chain reaction (RT-PCR) of 14 relapsing/remitting (RR) and 14 secondary progressive (SP) MS patients were studied in comparison with clinical manifestation of the disease. Serum concentrations of cytokines IL-12 and TNF-α were analyzed by enzyme-linked immunosorbent assay.

RESULTS:

Plasma samples from 25 of the 28 MS patients with estimated latent/persistent HHV-6 and/or HHV-7 infection were examined during relapse and remission/relative remission. HHV-6 reactivation was found in 4 of the 7 RRMS and 4 of the 7 SPMS patients, and HHV-7 reactivation was identified in 3 of the 7 RRMS and 1 of the 7 SPMS patients (all in relapse). In 2 of the 3 RRMS patients without viremia in relapse, HHV-6 mRNA transcription was detected. In RRMS and SPMS patients with active HHV-6 and HHV-7 infection in relapse, the serum concentrations of IL-12 and TNF-α were significantly higher than in those with latent virus infection.

CONCLUSIONS:

HHV-6 and HHV-7 reactivation could be implicated in the exacerbation of MS via activation of Th1 lymphocyte subsets.

Enhancement of chemokine function as an immunomodulatory strategy employed by human herpesviruses.

Herpes simplex virus (HSV) types 1 and 2 are highly prevalent human neurotropic pathogens that cause a variety of diseases, including lethal encephalitis. The relationship between HSV and the host immune system is one of the main determinants of the infection outcome. Chemokines play relevant roles in antiviral response and immunopathology, but the modulation of chemokine function by HSV is not well understood. We have addressed the modulation of chemokine function mediated by HSV. By using surface plasmon resonance and crosslinking assays we show that secreted glycoprotein G (SgG) from both HSV-1 and HSV-2 binds chemokines with high affinity. Chemokine binding activity was also observed in the supernatant of HSV-2 infected cells and in the plasma membrane of cells infected with HSV-1 wild type but not with a gG deficient HSV-1 mutant. Cell-binding and competition experiments indicate that the interaction takes place through the glycosaminoglycan-binding domain of the chemokine. The functional relevance of the interaction was determined both in vitro, by performing transwell assays, time-lapse microscopy, and signal transduction experiments; and in vivo, using the air pouch model of inflammation. Interestingly, and in contrast to what has been observed for previously described viral chemokine binding proteins, HSV SgGs do not inhibit chemokine function. On the contrary, HSV SgGs enhance chemotaxis both in vitro and in vivo through increasing directionality, potency and receptor signaling. This is the first report, to our knowledge, of a viral chemokine binding protein from a human pathogen that increases chemokine function and points towards a previously undescribed strategy of immune modulation mediated by viruses.

Human herpesvirus 6 and 7 reactivation and disease activity in multiple sclerosis.

Multiple sclerosis 

Anti-HHV-6 IgG titer significantly predicts subsequent relapse risk in multiple sclerosis.

 Multiple sclerosis

Japanese macaque encephalomyelitis: a spontaneous multiple sclerosis-like disease in a nonhuman primate.

Image by Getty Images via @daylife

Japanese macaque encephalomyelitis is associated with a novel simian herpesvirus

 Multiple sclerosis genes and risk factors