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Investigating the genetic architecture and pathogenesis of of Herpes Simplex encephalitis susceptibility

Objective

"Childhood herpes simplex encephalitis (HSE) is a potentially life-threatening complication of primary infection by herpes simplex virus-1 (HSV-1), a common virus that is innocuous in most children. HSE is the most common sporadic viral encephalitis in Western countries and acyclovir-treated patients often suffer from severe neurological sequels. The pathogenesis of HSE remained unknown until the recent discoveries of Mendelian single-gene mutations specifically impairing immunity to HSV-1 at least in a subset of children suffering from HSE. We have identified mutations in TLR3, UNC93B, TRIF and TRAF3 in patients with isolated HSE, suggesting that impaired type I interferon (IFN) production upon stimulation of TLR3 by dsRNA viral intermediates in the CNS underlies the pathogenesis of HSE in these patients. Despite the identification of these genes, only a minority of the patients tested carried these genetic defects. Hence we hypothesize that childhood HSE is a genetically heterogeneous disease and that other single gene inborn errors of immunity may explain HSE in other patients. As a first objective, we hope to identify novel HSE-causing genes following a candidate gene approach in patients with a cellular phenotype. The TLR3-IFN pathway will be tested and the known genes sequenced. For those without any mutations in known genes, alternative approaches such as cDNA complementation and RNA sequencing will be carried out. In addition, we also aim to understand the cellular basis of the pathogensis of HSE as most our studies have been carried out on patients’ fibroblasts. We hope to characterize the TLR3-dependent type I IFN production in response to dsRNA and HSV-1 in CNS resident cells by differentiating patient-derived fibroblast induced pluripotent stem (iPS) cells into neurons, oligodendrocytes, and astrocytes. Investigating the anti-HSV-1 immunity in the relevant CNS cells types will be important in furthering our understanding of HSE pathogenesis."

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation

Call for proposal

FP7-PEOPLE-2010-RG
See other projects for this call

Funding Scheme

MC-ERG - European Re-integration Grants (ERG)

Coordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 30 000
Administrative Contact
Tatjana Palalic (Ms.)