Cancer Onset May Be Caused by Immune System Fighting Viruses | GEN

 "The development of an advanced immune system to fight off microbial pathogens is a considerable part of the evolutionary success of multicellular organisms. Yet, like most success stories there is always a flip side. New evidence from investigators at the University of Colorado (CU) Cancer Center shows how the action of various immunity-based enzymes can spill over onto the host genome when trying to fight off various viral pathogens—ultimately leading to cancer-causing DNA mutations. Findings from the new study were published recently in Viruses, in an article entitled “Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression.”"

Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases."



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CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-[alpha] : Nature Medicine : Nature Research

Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.

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TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. - PubMed - NCBI

Viral infection during fetal or neonatal stages increases the risk of developing neuropsychiatric disorders such as schizophrenia and autism spectrum disorders. Although neurons express several key regulators of innate immunity, the role of neuronal innate immunity in psychiatric disorders is still unclear. Using cultured neurons and in vivo mouse brain studies, we show here that Toll-like receptor 3 (TLR3) acts through myeloid differentiation primary response gene 88 (MYD88) to negatively control Disrupted in schizophrenia 1 (Disc1) expression, resulting in impairment of neuronal development. Cytokines are not involved in TLR3-mediated inhibition of dendrite outgrowth. Instead, TLR3 signaling suppresses expression of several psychiatric disorder-related genes, including Disc1 The impaired dendritic arborization caused by TLR3 activation is rescued by MYD88 deficiency or DISC1 overexpression. In addition, TLR3 activation at the neonatal stage increases dendritic spine density, but narrows spine heads at postnatal day 21 (P21), suggesting a long-lasting effect of TLR3 activation on spinogenesis. Our study reveals a novel mechanism of TLR3 in regulation of dendritic morphology and provides an explanation for how environmental factors influence mental health.



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Extracellular vesicles and viruses: Are they close relatives?

Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell–cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery."

Reduced maternal levels of common viruses during pregnancy predict offspring psychosis: potential role of enhanced maternal immune activity? - PubMed - NCBI

Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case-control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N=43) and pregnant women with healthy offspring (controls, N=95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p<0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis.



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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment: Immunity

Highlights
•Viruses induce depressive behavior and ISG15 expression at the blood-brain barrier
•IFNAR1 expression on neural cells is not involved in IFN-β-induced sickness behavior
•IFNAR1 expression on brain endothelial and epithelial cells drives behavioral changes
•Brain endothelia- and epithelia-derived CXCL10 inhibits hippocampal synaptic plasticity

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy."



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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment: Immunity

 Highlights 

•Viruses induce depressive behavior and ISG15 expression at the blood-brain barrier
•IFNAR1 expression on neural cells is not involved in IFN-β-induced sickness behavior
•IFNAR1 expression on brain endothelial and epithelial cells drives behavioral changes
•Brain endothelia- and epithelia-derived CXCL10 inhibits hippocampal synaptic plasticity

Summary 

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy."



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Viruses Have Their Own Version of CRISPR - The Atlantic

Dormant viral genes may awaken to cause ALS

Scientists at the National Institutes of Health discovered that reactivation of ancient viral genes embedded in the human genome may cause the destruction of neurons in some forms of amyotrophic lateral sclerosis (ALS). The results, published in Science Translational Medicine, suggest a link between human endogenous retroviral genes (HERVs) and ALS. The findings also raise the question of whether antiretroviral drugs, similar to those used for suppressing HIV, may help some ALS patients.

For generations, humans have been passing on genetic remnants of HERV infections that may have happened millions of years ago. Although nearly eight percent of the normal human genome is made up of these genes, very little is known about their role in health and disease.

A new virus in liver cancer

In the genome of tumour cells of 11 patients, the scientists observed the insertion of a viral DNA segment from adeno-associated virustype 2, known as AAV2. This virus has been considered non-pathogenic for humans until now. In order to confirm the virus's involvement in the cancer, the research team compared tumour tissues with normal tissues. They thus confirmed their hypothesis: the integration of viral DNA was found more often in tumour cells than in healthy cells in these 11 patients. Moreover, 8 of these patients did not have cirrhosis, and 6 of them presented no known risk factors for liver cancer.

Stealth Adapted Viruses – Possible Drivers of Major Neuropsychiatric Illnesses Including Alzheimer’s Disease

Mainstream neurologists and psychiatrists have largely refrained from serious
consideration of a virus cause of common brain diseases. This is mainly because
of the general lack of any accompanying immune system stimulated inflammatory reaction within the brain. This article exposes a weakness in this argument by describing the process of “stealth adaptation” of viruses. Deletion or mutation of relatively few virus components can result in derivative viruses, which are no longer effectively recognized by the cellular immune system. Consequently, there is no triggering of the inflammatory response. Furthermore, the brain is uniquely susceptible to symptomatic illness caused by stealth adapted viruses.
An understanding of stealth adaptation greatly expands the potential scope of
viral illnesses. It also underscores the value of using virus cultures as a diagnostic tool and of taking appropriate measures to avoid transmission of infection. More
importantly, therapeutic measures are available for suppressing both stealth
adapted and conventional virus infections through enhancement of the alternative
cellular energy (ACE) pathway. Such measures are available for clinical evaluation in treating many of the major illnesses affecting the brain, including Alzheimer’s
disease.

Immune alterations in acute bipolar depression. - PubMed - NCBI

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.

Mount Sinai scientists establish link between ALS and the body's response to viral infection | EurekAlert! Science News

A key protein previously implicated in Lou Gehrig's disease and other
neurological diseases plays an important role in the response to viral
infection, according to a study led by scientists from the Icahn School
of Medicine at Mount Sinai published today in Nature Immunology.


Neurological diseases have long been associated with inflammation,
part of the body's response to injury or infection that occurs when
immune cells home in to attack invaders like bacteria and viruses, and
to drive healing, but the link between them has not been understood.
This new study result suggests that genetic changes take away the
ability of a protein called senataxin to moderate the inflammatory
response to certain viral infections, possibly leading to persistent
inflammation that could aggravate disease progression.
Using cutting-edge genomic tools, the scientists found that
senataxin is deployed to quench the body's natural antiviral response at
a specific point; without such control, prolonged exposure to the
antiviral response can lead to inflammation. People with
senataxin-related forms of ALS and ataxia have a defective SETX gene
that leads to a dysfunctional form of the protein.

National Science Foundation (NSF) News - The 'intraterrestrials': New viruses discovered in ocean depths - US National Science Foundation (NSF)

Strange creatures live in the deep sea, but few are odder than the viruses that inhabit deep ocean methane seeps and prey on single-celled microorganisms called archaea.
The least understood of life's three primary domains, archaea thrive in the most extreme environments on the planet: near hot ocean rift vents, in acid mine drainage, in the saltiest of evaporation ponds and in petroleum deposits deep underground.
Virus in the deep blue sea
While searching the ocean's depths for evidence of viruses, scientists have found a remarkable new one, a virus that seemingly infects archaea that live beneath the ocean floor.
The researchers were surprised to discover that the virus selectively targets one of its own genes for mutation, and that this capacity is also shared by archaea themselves.
The findings appear today in a paper in the journal Nature Communications.

Epigenetics and animal virus infections

Epigenetics, modifications of the genome, heritable during cell division, that do not involve changes in DNA sequences include several mechanisms mainly: histone modifications, DNA
methylation and related modifications, non-coding RNAs (ncRNAs) and
others that regulate gene expression.

The past two decades has seen an explosion of interest for revealing mechanisms that
control epigenetic modifications, mainly based on the influence they
have on chromatin structure and their impact in biological processes
such as programmed DNA rearrangements, imprinting, germ line silencing,
developmentally cued stem cell division, and overall chromosomal
stability and identity. It has also become obvious that epigenetics
changes are fundamental in the interplay between viruses and their host
cells. Generally speaking, when retroviruses and DNA viruses integrate
their genomes into the host genome, they can stay latent by silencing
their genes or can be productive by activating them, and viral gene
expression can be regulated just like as the host. In fact, viral DNA
uses host transcription factors as well as epigenetic regulators, in
such a way that the effect of viral epigenetic control of its own gene
expression also extends to regulate host gene expression. At the same
time cells use similar mechanisms, transcription factors and epigenetic
modifications, in order to try to eliminate viral infections. In
summary, epigenetic mechanisms are involved in most of the virus-cell
interactions.

The goal of this special issue is to bring
together key experimental and theoretical research linking
state-of-the-art knowledge of epigenetic mechanisms involved in
regulating virus-cell interactions.

Small Things Considered: Polintons; A Viral Missing Link?

The line between viruses and parasitic elements of the genome is thin and delicate, and probably often crossed. Parasitic elements that acquire the means to escape the host cell become viruses and, conversely, viruses can lose this ability and return to a more limited lifestyle as transposable elements (TEs). This back-and-forth occurs alongside a propensity for gene exchange, with genes acquired horizontally from various hosts, and at various periods of evolution.The result is that, although viruses and other "selfish" elements are obviously related, their relationship cannot be represented by the satisfying, graceful branches seen on phylogenetic trees depicting the evolution of more pedestrian organisms such as primates, for example. Instead, a virus or TE is like a quilt whose patches were added by different quilters, at different times. 

Mining for viral fragments in methylation enriched sequencing data.

Most next generation sequencing experiments generate more data than is usable for the experimental set up. For example, methyl-CpG binding domain (MBD) affinity purification based sequencing is often used for DNA-methylation profiling, but up to 30% of the sequenced fragments cannot be mapped uniquely to the reference genome. Here we present and evaluate a methodology for the identification of viruses in these otherwise unused paired-end MBD-seq data. Viral detection is accomplished by mapping non-reference alignable reads to a comprehensive set of viral genomes. As viruses play an important role in epigenetics and cancer development, 92 (pre)malignant and benign samples, originating from two different collections of cervical samples and related cell lines, were used in this study. These samples include primary carcinomas (n = 22), low- and high-grade cervical intraepithelial neoplasia (CIN1 and CIN2/3 - n = 2/n = 30) and normal tissue (n = 20), as well as control samples (n = 17). Viruses that were detected include phages, adenoviruses, herpesviridae and HPV. HPV, which causes virtually all cervical cancers, was identified in 95% of the carcinomas, 100% of the CIN2/3 samples, both CIN1 samples and in 55% of the normal samples. Comparing the amount of mapped fragments on HPV for each HPV-infected sample yielded a significant difference between normal samples and carcinomas or CIN2/3 samples (adjusted p-values resp. <10(-5), <10(-5)), reflecting different viral loads and/or methylation degrees in non-normal samples. Fragments originating from different HPV types could be distinguished and were independently validated by PCR-based assays in 71% of the detections. In conclusion, although limited by the a priori knowledge of viral reference genome sequences, the proposed methodology can provide a first confined but substantial insight into the presence, concentration and types of methylated viral sequences in MBD-seq data at low additional cost.

Frontiers | Induction of the pro-inflammatory NF-kB-sensitive miRNA-146a by human neurotrophic viruses | Virology

A remarkably wide variety of human neurotrophic viruses—ranging from herpes simplex 1 (HSV-1;Herpesviridae; dsDNA genome) to Hantavirus (HTV; Bunyaviridae; (−)ssRNA genome) to human immunodeficiency virus (HIV; Retroviridae; (+)ssRNA genome) are associated with the rapid up-regulation of the NF-kB-sensitive pro-inflammatory microRNA-146a (miRNA-146a) in the host shortly after infection. This significant miRNA-146a up-regulation appears to be beneficial to the infecting virus as part of an immune-evasion strategy. Interestingly, miRNA-146a is also significantly up-regulated in several human central nervous system (CNS) disorders. These include Alzheimer's disease (AD) and prion disease where miRNA-146a participates in pro-inflammatory and innate-immune signaling. This opinion paper will comment on some recently clarified roles for the NF-kB-regulated, pro-inflammatory miRNA-146a in viral-induced cellular dysfunction, and how anti-miRNA-146a and/or related therapeutic strategies may be beneficial in the clinical management of a broad spectrum of viral-mediated CNS disease.

Viral Virtuosos | The Scientist Magazine®

A diverse, abundant, and underappreciated viral community exists on and within us, from our skin to our eyes, blood, brain, and other organs—even within our own genomes.1 Unlike marauding Ebola-like viruses, these viruses establish a balanced coexistence that can persist for a host’s entire lifetime. This coexistence involves careful control of the viral life cycle: whereas Ebola virus infection is flashy, persistent infection is elegant.

Among other challenges, persistent viruses must effectively subvert the host immune response. To accomplish this, these viruses control both the timing and amount of viral replication. Such nuanced infectious cycles involve carefully choreographed viral gene expression that can foster completely different lifestyles depending on host cell type, cell-signaling events, or other factors. One important class of regulators that helps to mediate these lifestyle switches is the noncoding regulatory RNAs (ncRNAs), which today stand at the center of an ongoing mini-revolution in our understanding of gene-expression control.

Previously thought of as a simple decoder of genetic information—serving as an intermediate between DNA and protein—RNA is now known to engage in a bevy of other important biochemical activities. Despite differences in ncRNA sequence, size, and function, a theme is emerging: diverse biological processes rely on ncRNAs to balance the timing and magnitude of gene expression.2 In eukaryotes, microRNAs (miRNAs) represent the best-characterized ncRNAs. About 22 nucleotides in length, these small RNAs bind to and repress target messenger RNA (mRNA) transcripts, allowing for fine-tuning of gene expression. The human genome encodes hundreds of different miRNAs to regulate numerous biological functions, and recent research is revealing how the viruses of the human body use these miRNAs, as well as their own, to establish and maintain long-term persistent infections.