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The genetic dissection of herpes simplex encephalitis (HSE) in children

Final Report Summary - NOVELPID (The genetic dissection of herpes simplex encephalitis (HSE) in children)

Publishable summary

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus that causes asymptomatic infection in most people. The majority of primary infections with HSV-1 occurs between the ages of six months and six years however infections in adulthood have also been reported (1-4). Rarely, HSV-1 infections can cause complications leading to the development of Herpes simplex encephalitis (HSE), characterised by severe inflammation and cell destruction due to the replicating virus in the brain. HSE can occur at any age however the incidence seems to peak early in life, suggesting that childhood HSE reflects a complication in the primary infection of HSV-1. The prevalence of HSE is 2-4 cases in 100 000 people per year (3, 5, 6). HSE used to be a fatal disease however it can now be treated effectively with acyclovir although neurological sequelae persist in most survivors including mental retardation and seizures (2, 7).

In our grant entitled 'The genetic dissection of HSE in children', we hypothesise that at least a subset of childhood HSE patients suffer from a novel primary immunodeficiency specific to HSV-1. We have previously demonstrated this to be the case with the first descriptions of HSE patients harbouring genetic mutations in UNC93B and TLR3 leading to a specific susceptibility to HSE (8, 9). Therefore the objective in this particular grant is to identify other gene(s) involved in the host response to HSV-1 infection in childhood HSE patients. We will employ a two tiered approach in the search for the causative gene(s) - a candidate gene approach and a genome wide linkage study of consanguineous families. First, we will use a candidate gene approach to investigate the innate immune response of HSE patients by focusing on antiviral IFN-a/ß immunity. Secondly, in the absence of any apparent cellular defect using the candidate gene approach, a genome scan will be carried out on HSE patients of consanguineous families. We hope to shed light on the human genetics, immunology, and molecular basis of this disease.

HSE patients with UNC93B and TLR3 deficiencies share the cellular phenotype of impaired type I interferons (IFNs) production following stimulation with double-stranded RNA (dsRNA) and viruses. This has led us to focus on a specific UNC93B-TLR3-IFN pathway as being relevant to HSE immunity. Subsequently we have identified at least two other patients, P1 and P2, among our cohort of HSE patients with impaired production of type I IFN following viral and dsRNA activation. UNC93B and TLR3 deficiencies in these patients have been excluded based on sequence analysis pointing towards the likelihood of mutations in genes other than those we have already identified. Further immunological testing revealed that these patients' fibroblasts showed a specific decrease in interferon regulatory factor-3 (IRF3) dimerisation consistent with the lack of IFN production. Sequencing and expression of all known genes in this critical pathway is in progress under the assumption that a mutation lies in one of these genes.

In parallel, we have investigated other HSE patients, for whom UNC93B and TLR3 deficiencies have been excluded, by candidate gene sequencing to identify other mutations underlying HSE. Through this approach, we have identified two different heterozygous non-synonymous mutations in HSE4, a candidate gene in the TLR3 signalling pathway, in two unrelated HSE patients P3, and P4, which were not found in over 1200 healthy controls sequenced. In P3's fibroblasts, we observed impaired type I IFN production following TLR3 activation and virus infection. Further molecular studies in P3 have shown a specific decrease in IRF3 dimerisation consistent with the lack of type I IFN production following TLR3 stimulation. Moreover, P3's cells were more susceptible to viral infection as measured by viral replication and host cell mortality. Further molecular characterisation of P3's mutated allele suggested that the mutation is deleterious and dominant, predisposing to HSE. Characterisation of P4's mutation is currently in progress. Here, we describe for the first time autosomal dominant HSE4 deficiency resulting in susceptibility to HSE.

Infectious diseases, including viral infections, continue to be a problem today. The identification of gene(s) underlying HSE is bound to have immunological and clinical ramifications. The discovery of HSE genes will represent a molecular basis that confers specific protection to HSV-1 which will undoubtedly contribute to the better understanding of the disease process. Being able to identify the causative gene defect is crucial in these patients as it can improve their prognosis significantly. Currently, HSE patients suffer neurological consequences despite administration of acyclovir. The use of novel immuno-modulatory drugs in addition to antiviral therapy may lead to less severe sequelae or may even be life saving. The patient with HSE1 deficiency, for example, may have suffered less if recombinant IFN-a was administered along with acyclovir. The genetic dissection will illuminate our understanding of the aetiology of HSE, leading to improvement in the treatment of the patient

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