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Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

ABSTRACT: Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70 per cent of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis patients and from skin swabs of epidermal vesicles on non-encephalopathic patients. Phylogenetic analysis revealed high inter-host diversity and little population structure. In contrast, samples from different lesions in the same patient clustered with similar patterns of allelic variants. Comparison of consensus genome sequences shows HSV-1 has been freely recombining, except for distinct islands of linkage disequilibrium (LD). This suggests functional constraints prevent recombination between certain genes, notably those encoding pairs of interacting proteins. Distinct LD patterns characterised subsets of viruses recovered from CSF and skin lesions, which may reflect different evolutionary constraints in different body compartments. Functions of genes under differential constraint related to immunity or tropism and provide new hypotheses on tissue-specific mechanisms of viral infection and latency.

SUBMITTER: Lassalle F

PROVIDER: S-EPMC7031915 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

Lassalle Florent F Beale Mathew A MA Bharucha Tehmina T Williams Charlotte A CA Williams Rachel J RJ Cudini Juliana J Goldstein Richard R Haque Tanzina T Depledge Daniel P DP Breuer Judith J

Virus evolution 20200101 1

Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70 per cent of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis ...[more]

PMID: 32099667

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Project description:Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( -) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABABR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( -) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.

Project description:Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.

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Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

Publications

Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

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