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PLoS Pathogens Sep 2022Invasion of the brain by herpes simplex virus 1 (HSV1) can lead to the development of herpes simplex encephalitis (HSE) that is often associated with significant...
Invasion of the brain by herpes simplex virus 1 (HSV1) can lead to the development of herpes simplex encephalitis (HSE) that is often associated with significant morbidity and mortality regardless of therapeutic intervention. Both virus and host immune factors dictate HSE onset and progression. Because programmed cell death pathways including necroptosis are important antiviral defense mechanisms in HSV1-associated peripheral diseases, they might also play critical roles in HSV1 neuropathogenesis. HSV1-encoded ICP6 prevents receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis during infection of human cells, but it also acts as a species-dependent inducer of necroptosis in murine cells and thereby restricts virus replication. We therefore used an established mouse model of HSE to investigate RIPK3-mediated necroptosis impact on HSV1 neuropathogenesis. Following corneal HSV1 inoculation, RIPK3 knockout mice showed increased susceptibility to HSE when compared with wildtype mice indicating RIPK3 helps to limit HSE progression. RIPK3-mediated defense against HSE was found to be independent of the kinase domain necessary to drive necroptosis implicating that a death independent function of RIPK3 protects against HSE. Conversely the pro-necroptotic kinase function RIPK3 served to limit viral replication in corneal tissue implicating a tissue-specific RIPK3 function in limiting HSV1. Further evaluation of the kinase-independent mechanism to restrict HSE revealed that the RIPK3 signaling partner, caspase 8, contributes to limiting HSE neuropathogenesis. Increased HSE susceptibility from loss of caspase 8 and RIPK3 correlated with decreased levels of chemokines, cytokines, and antiviral lymphocytes recruitment to the brain. We conclude that RIPK3 contributes toward host control of HSV1 replication in a tissue-specific fashion. Whereas RIPK3-mediated necroptosis restricts virus replication within the cornea, kinase-independent induction of inflammation by RIPK3 in collaboration with caspase 8 restricts virus replication within the brain during HSE neuropathogenesis.
Topics: Animals; Antiviral Agents; Caspase 8; Chemokines; Encephalitis, Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Knockout; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 36121858
DOI: 10.1371/journal.ppat.1010857 -
Neurotherapeutics : the Journal of the... Jul 2016The study of neurological infections by viruses defines the field of neurovirology, which has emerged in the last 30 years and was founded upon the discovery of a number... (Review)
Review
The study of neurological infections by viruses defines the field of neurovirology, which has emerged in the last 30 years and was founded upon the discovery of a number of viruses capable of infecting the human nervous system. Studies have focused on the molecular and biological basis of viral neurological diseases with the aim of revealing new therapeutic options. The first studies of neurovirological infections can be traced back to the discovery that some viruses have an affinity for the nervous system with research into rabies by Louis Pasteur and others in the 1880s. Today, the immense public health impact of neurovirological infections is illustrated by diseases such as neuroAIDS, progressive multifocal leukoencephalopathy, and viral encephalitis. Recent research has seen the development of powerful new techniques for gene editing that promise revolutionary opportunities for the development of novel therapeutic options. In particular, clustered regulatory interspaced short palindromic repeat-associated 9 system provides an effective, highly specific and versatile tool for targeting DNA viruses that are beginning to allow the development of such new approaches. In this short review, we discuss these recent developments, how they pertain to neurological infections, and future prospects.
Topics: CRISPR-Cas Systems; Central Nervous System Viral Diseases; Encephalitis, Herpes Simplex; Gene Editing; Genetic Therapy; HIV Infections; Herpesvirus 1, Human; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 27150390
DOI: 10.1007/s13311-016-0439-1 -
Journal of Neuroimmunology May 2023To systematically evaluate the risk factors of post-encephalitis epilepsy (PEE). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To systematically evaluate the risk factors of post-encephalitis epilepsy (PEE).
METHODS
Systematic computerized searches of databases such as Cochrane Library, PubMed and EMBASE were performed. The meta-analysis of pooled odds ratios and 95% confidence intervals for PEE risk were calculated.
RESULTS
Sixteen studies with 2504 patients were included for meta-analysis. The results showed that PEE was associated with coma, seizure, status epilepticus, cranial MRI abnormality, focal EEG abnormality, and positive herpes simplex virus (HSV) in cerebrospinal fluid (CSF).
CONCLUSION
Coma, seizures or status epilepticus, abnormal MRI and focal EEG, and HSV in CSF were the risk factors of PEE.
Topics: Humans; Coma; Epilepsy; Encephalitis, Viral; Seizures; Risk Factors; Status Epilepticus; Encephalitis; Encephalitis, Herpes Simplex
PubMed: 37094438
DOI: 10.1016/j.jneuroim.2023.578089 -
Journal of Neurovirology Oct 2023Little is known about concomitant central nervous system (CNS) infections by more than one virus. Current diagnostics are based on molecular tests for particular...
Little is known about concomitant central nervous system (CNS) infections by more than one virus. Current diagnostics are based on molecular tests for particular pathogens making it difficult to identify multi-viral infections. In the present study, we applied DNA- and RNA-based next-generation sequencing metagenomics (mNGS) to detect viruses in cerebrospinal fluids from 20 patients with herpes simplex encephalitis. Coinfection was detected in one patient: sequences in cerebrospinal fluids matched enterovirus A (2.660 reads; 4% of recovered genome) and enterovirus B (1.571 reads; 13% of recovered genome). Subsequent PCR combined with serotyping allowed to identify human echovirus 6, a representative of enterovirus B. Several other mNGS hits (human pegivirus, Merkel cell polyomavirus, human papillomavirus type 5) were not considered to represent a genuine signal as they could not be confirmed by specific RT-PCR/PCR. HSV DNA, while being detectable by PCR in every patient, was detected by mNGS in only one. In conclusion, contaminations and false signals may complicate mNGS interpretation; however, the method can be useful in diagnostics of viral coinfections in CNS, particularly in the case of rare pathogens.
Topics: Humans; Coinfection; Encephalitis, Herpes Simplex; Virus Diseases; Polymerase Chain Reaction; Enterovirus B, Human; Central Nervous System Infections; DNA; High-Throughput Nucleotide Sequencing
PubMed: 37490185
DOI: 10.1007/s13365-023-01157-9 -
Gut Microbes 2022Herpes simplex encephalitis (HSE), a complication of herpes simplex virus type I (HSV-1) infection causes neurological disorder or even death in immunocompromised adults...
Herpes simplex encephalitis (HSE), a complication of herpes simplex virus type I (HSV-1) infection causes neurological disorder or even death in immunocompromised adults and newborns. However, the intrinsic factors controlling the HSE outcome remain unclear. Here, we show that HSE mice exhibit gut microbiota dysbiosis and altered metabolite configuration and tryptophan-nicotinamide metabolism. HSV-1 neurotropic infection activated microglia, with changed immune properties and cell numbers, to stimulate antiviral immune response and contribute substantially to HSE. In addition, depletion of gut microbiota by oral antibiotics (ABX)-treatment triggered the hyper-activation of microglia, which in turn enhanced inflammatory immune response, and cytokine production, resulting in aggregated viral burden and HSE pathology. Furthermore, exogenous administration of nicotinamide n-oxide (NAMO), an oxidative product of nicotinamide derived from gut microbiota, to ABX-treated or untreated HSE mice significantly diminished microglia-mediated proinflammatory response and limited HSV-1 infection in CNS. Mechanistic study revealed that HSV-1 activates microglia by increasing mitochondrial damage via defective mitophagy, whereas microbial metabolite NAMO restores NAD+-dependent mitophagy to inhibit microglia activation and HSE progression. NAMO also prevented neuronal cell death triggered by HSV-1 infection or microglia-mediated microenvironmental toxicity. Finally, we show that NAMO is mainly generated by neomycin-sensitive bacteria, especially and . Together, these data demonstrate that gut microbial metabolites act as intrinsic restrictive factors against HSE progression via regulating mitophagy in microglia, implying further exploration of bacterial or nutritional approaches for treating neurotropic virus-related neurodegenerative diseases.
Topics: Animals; Encephalitis, Herpes Simplex; Gastrointestinal Microbiome; Mice; Microglia; Mitophagy; Niacinamide
PubMed: 35793266
DOI: 10.1080/19490976.2022.2096989 -
Postgraduate Medical Journal Oct 2002Acute encephalitis constitutes a medical emergency. In most cases, the presence of focal neurological signs and focal seizures will distinguish encephalitis from... (Review)
Review
Acute encephalitis constitutes a medical emergency. In most cases, the presence of focal neurological signs and focal seizures will distinguish encephalitis from encephalopathy. Acute disseminated encephalomyelitis is a non-infective inflammatory encephalitis that may require to be treated with steroids. Acute infective encephalitis is usually viral. Herpes simplex encephalitis (HSE) is the commonest sporadic acute viral encephalitis in the Western world. Magnetic resonance imaging of brain is the investigation of choice in HSE and the diagnosis may be confirmed by the polymerase chain reaction test for the virus in the cerebrospinal fluid. In this article, we review the diagnosis, investigations, and management of acute encephalitis. With few exceptions (for example, aciclovir for HSE), no specific therapy is available for most forms of viral encephalitis. Mortality and morbidity may be high and long term sequelae are known among survivors. The emergence of unusual forms of zoonotic encephalitis has posed an important public health problem. Vaccination and vector control measures are useful preventive strategies in certain arboviral and zoonotic encephalitis. However, we need better antiviral therapy to meet the challenge of acute viral encephalitis more effectively.
Topics: Acute Disease; Biopsy; Cytomegalovirus Infections; Diagnostic Imaging; Electroencephalography; Encephalitis, Herpes Simplex; Encephalitis, Viral; Humans; Magnetic Resonance Imaging; Medical History Taking; Paramyxoviridae Infections; Spinal Puncture
PubMed: 12415078
DOI: 10.1136/pmj.78.924.575 -
Revista Chilena de Infectologia :... Dec 2012
Topics: Encephalitis, Herpes Simplex; Female; Herpes Simplex; Herpesvirus 1, Human; Humans
PubMed: 23412050
DOI: 10.4067/S0716-10182012000700026 -
Neurological Sciences : Official... Apr 2022Suid herpesvirus type 1 (SHV1) is a type of neurotropic virus able to infect various species. However, the clinical cases of human SHV1 encephalitis are still rarely...
BACKGROUND
Suid herpesvirus type 1 (SHV1) is a type of neurotropic virus able to infect various species. However, the clinical cases of human SHV1 encephalitis are still rarely reported, and the clinical characteristics, treatment, and prognosis of human SHV1 encephalitis are still unclear.
METHODS
In this study, we reported 2 cases of human encephalitis associated with SHV1 infection and reviewed the other 18 cases from the literatures. A total of 20 cases with human SHV1 encephalitis were summarized and re-analyzed.
RESULTS
Nineteen of 20 patients had a history of swine-related occupational exposure before illness onset. All patients initially presented with influenza-like symptoms and then developed seizures, disturbed consciousness, and endophthalmitis. All patients with clinical outcome of modified Rankin Scale of 5 or 6 suffered from rapid progressive respiratory failure. The results of cerebrospinal fluid (CSF) indicated aseptic or viral infection. MRI findings of SHV1 encephalitis were prone to distribute in temporal-frontal and insular cortex, which was similar to the pattern of herpes simplex virus encephalitis, while some cases with involvements of gray matter nuclei had a high rate of mortality. Metagenomic next-generation sequencing (mNGS) revealed that all patients had unique SHV1 sequences with variable reads in the CSF.
CONCLUSIONS
The variant SHV1 can cause a new type of human viral encephalitis, characterized by acute, fulminating, and catastrophic central nervous system infection. Rapid progressive respiratory failure and extensive lesions of deep gray matter nuclei might be indicators to poor prognosis. No approved treatments for the encephalitis are available, but it is possible to diagnose encephalitis quickly by mNGS.
Topics: Animals; Encephalitis, Herpes Simplex; Encephalitis, Viral; Herpesvirus 1, Human; Herpesvirus 1, Suid; Herpesvirus 3, Human; Humans; Magnetic Resonance Imaging; Swine
PubMed: 34647219
DOI: 10.1007/s10072-021-05633-0 -
PLoS Pathogens Feb 2021Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although...
Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1β and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.
Topics: Animals; Brain; CARD Signaling Adaptor Proteins; Cells, Cultured; Chemokines, CC; Chlorocebus aethiops; Disease Models, Animal; Encephalitis, Herpes Simplex; Female; Inflammasomes; Inflammation Mediators; Interleukin-1beta; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Vero Cells
PubMed: 33524073
DOI: 10.1371/journal.ppat.1009285 -
Current Opinion in Neurology Jun 2014This review describes the main types of autoimmune encephalitis with special emphasis on those associated with antibodies against neuronal cell surface or synaptic... (Review)
Review
PURPOSE OF REVIEW
This review describes the main types of autoimmune encephalitis with special emphasis on those associated with antibodies against neuronal cell surface or synaptic proteins, and the differential diagnosis with infectious encephalitis.
RECENT FINDINGS
There is a continuous expansion of the number of cell surface or synaptic proteins that are targets of autoimmunity. The most recently identified include the metabotropic glutamate receptor 5 (mGluR5), dipeptidyl-peptidase-like protein-6 (DPPX), and γ-aminobutyric acid-A receptor (GABAAR). In these and previously known types of autoimmune encephalitis [N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid-B receptor (GABABR), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 (CASPR2)], the prodromal symptoms or types of presentations often suggest a viral encephalitis. We review here clues that help in the differential diagnosis with infectious encephalitis. Moreover, recent investigations indicate that viral encephalitis (e.g., herpes simplex) can trigger synaptic autoimmunity. In all these disorders, immunotherapy is usually effective.
SUMMARY
Autoimmune encephalitis comprises an expanding group of potentially treatable disorders that should be included in the differential diagnosis of any type of encephalitis.
VIDEO ABSTRACT
http://links.lww.com/CONR/A25,
Topics: Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Brain; Brain Diseases; Diagnosis, Differential; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Encephalitis; Encephalitis, Herpes Simplex; Hashimoto Disease; Humans; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Membrane Proteins; Nerve Tissue Proteins; Potassium Channels; Proteins; Receptor, Metabotropic Glutamate 5; Receptors, GABA-A; Receptors, Glutamate; Tuberculosis, Central Nervous System
PubMed: 24792345
DOI: 10.1097/WCO.0000000000000087