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The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice

ABSTRACT: Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (RelC307X) that drives lethal HSE in 60% of HSV-1-infected RelC307X mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in RelC307X-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in RelC307X mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.

SUBMITTER: Mancini M

PROVIDER: S-EPMC8551191 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice

Project description:c-Rel is a transcription factor and a subunit of NF-kΒ encoded by the Rel gene. We previously demonstrated that a truncating cysteine to stop codon mutation at amino acid position 307 of c-Rel (RelC307X) results in susceptibility to herpes simplex virus type 1 (HSV-1). Approximately 60% of mutant RelC307X mice succumb to lethal herpes simplex encephalitis (HSE) in the hindbrain between days 6 and 9 postinfection, compared to resistant wild-type (Rel+/+) controls. Here, we performed dual host-pathogen RNA sequencing on Rel+/+ and RelC307X brainstems to measure differential viral and host gene expression that may underlie HSE susceptibility in mutant mice. Briefly, brainstems were harvested from Rel+/+ and RelC307X mice prior to HSE symptom onset at day 5 post-HSV-1 infection, compared to brainstems collected from non-infected control mice. Total RNA was isolated from bulk tissue using TRIzol (Invitrogen) and further column-purified using the RNeasy Mini Kit (Qiagen). RNA quality was assessed using Bioanalyzer RNA Pico chips (Agilent), and libraries were prepared following rRNA depletion. Libraries were sequenced on an Illumina HiSeq 2500 sequencer in paired-end 50bp configuration. Sequencing reads were aligned to both mouse and HSV-1 strain 17 reference genomes to obtain both host and viral gene expression counts. In total, 5 Rel+/+ and 6 RelC307X brainstem samples were analyzed at day 5 post-infection, and 4 Rel+/+ and 4 RelC307X independent non-infected samples as controls. Day 5 HSV-1-infected samples were further subdivided into high- or low-responder within both genotype groups based in part on the level of viral and host defence gene expression in each sample.

2021-10-29 | GSE168799 | GEO

The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice

Project description:The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice

| PRJNA714059 | ENA

CXCL11 production in cerebrospinal fluid distinguishes herpes simplex meningitis from herpes simplex encephalitis.

Project description:BackgroundThe closely related herpes simplex viruses 1 and 2 can cause inflammations of the central nervous system (CNS), where type 1 most often manifest as encephalitis (HSE), and type 2 as meningitis (HSM). HSE is associated with severe neurological complications, while HSM is benign in adults. We proposed that studying the chemokine and cytokine production in cerebrospinal fluid (CSF) and serum could indicate why two closely related viruses exhibit different severity of their accompanied CNS inflammation.MethodsSecretion patterns of 30 chemokines and 10 cytokines in CSF of adult patients with acute HSE (n = 14) and HSM (n = 20) in the initial stage of disease were analyzed and compared to control subjects without viral central nervous system infections and to levels in serum.ResultsMost measured chemokines and cytokines increased in CSF of HSE and HSM patients. Overall, the CSF chemokine levels were higher in CSF of HSM patients compared to HSE patients. However, only five chemokines reached levels in the CSF that exceeded those in serum facilitating a positive CSF-serum chemokine gradient. Of these, CXCL8, CXCL9, and CXCL10 were present at high levels both in HSE and HSM whereas CXCL11 and CCL8 were present in HSM alone. Several chemokines were also elevated in serum of HSE patients but only one in HSM patients. No chemokine in- or efflux between CSF and serum was indicated as the levels of chemokines in CSF and serum did not correlate.ConclusionsWe show that HSM is associated with a stronger and more diverse inflammatory response in the CNS compared to HSE in the initial stage of disease. The chemokine patterns were distinguished by the exclusive local CNS production of CXCL11 and CCL8 in HSM. Inflammation in HSM appears to be restricted to the CNS whereas HSE also was associated with systemic inflammation.

| S-EPMC5504603 | biostudies-literature

Heterozygous SNORA31 mutations in patients with herpes simplex encephalitis

Project description:Pseudo-seq was used to measure differences in the extent of pseudouridine (Ψ) modification in rRNA from human cell lines with heterozygous, and homozygous disruptions of SNORA31.

2019-10-14 | GSE102078 | GEO

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis.

Project description:Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The use of intravenous acyclovir together with improved diagnostic technologies such as PCR and magnetic resonance imaging has resulted in a reduction in the mortality rate to close to 20%. However, 70% of surviving patients still do not recover complete neurological functions. Thus, there is an urgent need to develop more effective treatments for a better clinical outcome. It is well recognized that cerebral damage resulting from HSE is caused by viral replication together with an overzealous inflammatory response. Both of these processes constitute potential targets for the development of innovative therapies against HSE. In this review, we discuss recent progress in therapy that may be used to ameliorate the outcome of patients with HSE, with a particular emphasis on immunomodulatory agents. Ideally, the administration of adjunctive immunomodulatory drugs should be initiated during the rise of the inflammatory response, and its duration should be limited in time to reduce undesired effects. This critical time frame should be optimized by the identification of reliable biomarkers of inflammation.

| S-EPMC7018500 | biostudies-literature

A novel bioluminescent herpes simplex virus 1 for in vivo monitoring of herpes simplex encephalitis.

Project description:Herpes simplex virus 1 (HSV-1) is responsible for herpes simplex virus encephalitis (HSE), associated with a 70% mortality rate in the absence of treatment. Despite intravenous treatment with acyclovir, mortality remains significant, highlighting the need for new anti-herpetic agents. Herein, we describe a novel neurovirulent recombinant HSV-1 (rHSV-1), expressing the fluorescent tdTomato and Gaussia luciferase (Gluc) enzyme, generated by the Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) (CRISPR-Cas9) system. The Gluc activity measured in the cell culture supernatant was correlated (P = 0.0001) with infectious particles, allowing in vitro monitoring of viral replication kinetics. A significant correlation was also found between brain viral titers and Gluc activity in plasma (R2 = 0.8510, P < 0.0001) collected from BALB/c mice infected intranasally with rHSV-1. Furthermore, evaluation of valacyclovir (VACV) treatment of HSE could also be performed by analyzing Gluc activity in mouse plasma samples. Finally, it was also possible to study rHSV-1 dissemination and additionally to estimate brain viral titers by in vivo imaging system (IVIS). The new rHSV-1 with reporter proteins is not only as a powerful tool for in vitro and in vivo antiviral screening, but can also be used for studying different aspects of HSE pathogenesis.

| S-EPMC8455621 | biostudies-literature

Autoimmune post-herpes simplex encephalitis of adults and teenagers.

Project description:ObjectiveTo report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children.MethodsProspective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously.ResultsAmong the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037).ConclusionIn teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

| S-EPMC4653102 | biostudies-literature

Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report.

Project description: Not available

| S-EPMC3806918 | biostudies-literature

Herpes simplex virus encephalitis is a trigger of brain autoimmunity.

Project description:In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity.

| S-EPMC3961499 | biostudies-literature

Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

Project description:Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

| S-EPMC4880288 | biostudies-literature

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