NOVELPID

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

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 Obiettivo del progetto (Objective)

'Herpes simplex encephalitis (HSE) is a rare disease affecting young children as well as adults due to primary infection with herpes simplex virus-1 (HSV-1). HSV-1 is a nearly ubiquitous virus commonly infecting humans however most do not develop HSE, suggesting that these children possess an underlying genetic susceptibility to HSV-1. In addition, familial forms of HSE have been described, and in our HSE epidemiological study a relatively high incidence of consanguinity was found among HSE patients supporting the notion of a genetic contribution to disease manifestation. Notably, these patients are otherwise healthy and able to mount a normal adaptive immune response to HSV-1, pointing to the likelihood that they harbor an unidentified form of primary immunodeficiency disease affecting their innate immune system. We have recently identified the first two genetic etiologies UNC93B and TLR3 deficiencies in HSE patients validating our hypothesis. Here we propose to use a candidate gene approach to identify other gene(s) involved in HSE by cellular phenotyping and physical mapping. The cellular phenotyping will focus on one of the major components of antiviral innate immunity, namely, the production of and response to interferon-α/β (IFN-α/β). Patients with mutations in UNC93B and TLR3 show reduced IFN production after viral and double-stranded RNA stimulation, revealing this specific UNC93B-TLR3-IFN pathway as relevant to HSE immunity. Hence, HSE patients will be screened for IFN production in response to HSV-1 and Toll-like receptor agonists, and the causative genes identified following a candidate gene approach. In parallel, physical mapping has been initiated following the results of a genome scan of consanguineous families with HSE. The identification of genes involved in HSE will present important biological and medical implications, providing a dissection of immunity to HSV-1 in natural conditions and a rational understanding of HSE pathogenesis.'

Introduzione (Teaser)

Viral infections can usually be treated successfully. However, in a small number of cases, a gene defect may result in more serious complications.

Descrizione progetto (Article)

Herpes simplex virus-1 usually infects young children between six months and six years old. Sometimes adults are also infected, but at a much lower incidence and the infection is normally without symptoms. On rare occasions, Herpes simplex encephalitis (HSE) may develop. This can happen at any age and is characterised by serious inflammation and cell destruction by virus replication. Because this seems to happen mostly in the early years, childhood HSE points to a complication in the primary infection of HSV-1. And although it is now treated with acyclovir, HSE patients still suffer neurological consequences, which can prove as serious as mental retardation.

'The genetic dissection of herpes simplex encephalitis (HSE) in children' (Novelpid) project hypothesised that a subset of childhood HSE patients has an underlying genetic susceptibility and a primary immune deficiency that is particular to HSV-1. Based on this, the objective was to undertake a genetic dissection to throw light on the aetiology of HSE. An epidemiological study found a high incidence of kinship among HSE patients, which supports the idea of genetics contributing to expression of the disease. So identifying the gene or genes involved in 'triggering' HSE in children can offer greater insight into the disease process and promises a better prognosis for these patients.

Research validated the hypothesis when the first two genetic aetiologies, UNC93B and TLR3 deficiencies, were identified in HSE patients. The genetic mutations here cause a specific susceptibility to HSE. The team took a two-tiered approach in the search for the causative gene(s): a candidate gene approach was used first to detect cellular defects. In the absence of that, a genome wide linkage study of related families was done.

By investigating human genetics, immunology and the molecular basis of this disease, Novelpid discovered that HSE patients with UNC93B and TLR3 deficiencies share the cellular phenotype of impaired production of type I interferons (IFNs). This turned the focus to a specific UNC93B-TLR3-IFN pathway as being relevant to HSE immunity. This project described for the first time an autosomal dominant deficiency that leads to HSE susceptibility.