Why infection with herpes virus leads to encephalitis in a minority of children?

Why infection with herpes virus leads to encephalitis in a minority of children?
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Herpes Simplex encephalitis as an immune deficiency.

Herpes Simplex virus type 1 (HSV-1) infection is very common and usually mild. In most individuals, primary infection results in a cold sore and is followed by asymptomatic periods (latent infection) with stress-linked recurrences (reactivation). Exceptionally, in 1 to 4 individuals per million per year, HSV-1 can cause encephalitis (HSE), a very severe disease characterized by intense viral replication in brain cells which induces a cytopathic effect and tissue necrosis.

Susceptibility to HSE in children was shown to result from very rare mutations in genes directly involved in a specific immune pathway (the Toll-like receptor 3 – interferon pathway), which is essential and non-redundant for early detection of the virus in the brain. These mutations lead to insufficient interferon production and increase viral load, thereby causing encephalitis. However, the mutations identified so far explain only a limited proportion of child HSE.

The study in brief.

Over the years, our group has collected genetic material from individuals with rare, particularly severe and/or difficult to treat forms of infections, including HSE. The goal is to identify novel genetic variants in these individuals and understand by which mechanisms they impair immune responses and lead to such infections.

In this study, we identified a novel variant in a two years-old child with HSE, which was associated with impaired IFN production and increased viral replication in human induced pluripotent stem cells-derived neuronal cells. The link between the mutation and the immune phenotype was further supported by using the CRISPR-Cas 9 technology. Indeed, correction of mutation in cells from the affected child allowed to restore antiviral immunity, whereas introduction of the mutation in wild-type cells from her father impaired this function.

In contrast with previous studies, in which the variants associated with HSE were causing a “loss-of-function” (deficient Interferon production), this new variant is proposed to cause a “gain-of-function” in an enzyme whose role is to degrade proteins. Specifically, we suggest that this variant may induce excessive degradation of a protein which is essential for interferon production.

What challenges did we face?

A challenging issue was the production of induced pluripotent stem cells from the patient with HSE and family members and their derivation into neuronal cells. The process, which is very time consuming, requires specific skills. Specifically, neurons do not reproduce, so that a large number of precursors is needed to ensure a sufficient amount of viable mature cells. Finally, the study is based on few individuals carrying the mutation of interest, thereby limiting the ability to perform relevant statistical analyses.

 

Why is this research important?

Identification of variants involved in genes that are not directly involved in immune pathways, but rather regulate such pathway, would increase the scope of future research.

 

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Immunogenetics
Life Sciences > Biological Sciences > Immunology > Immunogenetics
Infectious Diseases
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Infectious Diseases

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