Fatality of Herpes Simplex Encephalitis in Children Revealed

Defects in a single protein involved in cell death may impair the immune system’s ability to combat herpes simplex encephalitis in the central nervous system, according to new research that examines a pediatric infection and explains how the flawed protein can lead to a rare but severe form of encephalitis. The findings were reported in the journal Science Immunology.

Herpes simplex encephalitis develops when the herpes simplex virus-1 invades the brain. It is a sneaky and insidious infection, with non-specific symptoms that can delay diagnosis. Sleepiness, lethargy, and fever are some of the symptoms.

Despite the use of antiviral drugs, the illness can progress and become one of the most lethal of the central nervous system. Seizures are common in children suffering from herpes simplex encephalitis. Infected neonates can experience a quick decline. Infants and older children are frequently exposed to the virus through close contact with someone who has a cold sore and is shedding herpes simplex-1. Sharing dining utensils, towels, or other items that might easily house the live virus is another route of transmission.

An international team of experts investigated the herpes simplex-1 infection of a minor kid who had developed herpes simplex encephalitis in an unusual case study that included a gene hunt for the DNA roots underlying susceptibility. Previous research revealed that herpes simplex encephalitis in children is caused by genetic abnormalities in the synthesis or response to type 1 interferon, a crucial activator of antiviral immunity.

However, Zhiyong Liu and colleagues at Rockefeller University in New York City, collaborating with experts from numerous institutions in the United States and France, discovered something that contradicted conventional thought and did not involve genetic abnormalities in the generation or response to type 1 interferon.

Their initial step toward discovery was to sequence the entire exome of proteins from the little girl who acquired herpes simplex encephalitis. Whole exome sequencing is a genomic approach that involves sequencing the entire genome’s protein-coding regions.
The scientists discovered two gene variants that carry the blueprint for a crucial protein called RIPK3, which regulates the initiation of cell death independent of type I interferon. While type 1 interferon can fight invading viruses, infected cells must be killed by a healthy RIPK3. If this does not occur, the virus is free to take over the central nervous system.

The discovery is significant because it sheds light on what molecular mechanisms go wrong in some children with herpes simplex encephalitis. The virus not only infiltrates the brain, but the illness is also notable for its high fatality rate, which is estimated to be over 20% even when patients are treated with an antiviral. Despite previous research linking susceptibility to inborn immune defects that were thought to impact the generation or sensing of type I interferon, the multinational team concluded that the likely culprit is a defective RIPK3 protein.

Herpes simplex encephalitis is the most prevalent single cause of viral encephalitis in newborns and children, according to the Centers for Disease Control and Prevention. Worse, whether treated or not, infection in newborns and children is closely connected to significant morbidity and mortality. The researchers discovered that the faulty RIPK3 protein generated various biological issues, which resulted in enhanced viral proliferation.

“The patient’s human pluripotent stem cell-derived cortical neurons displayed impaired cell death and enhanced viral growth after herpes simplex-1 infection,” Liu wrote in the Science Immunology article. The patient with herpes simplex encephalitis had compound heterozygous mutations in RIPK3, a key cytoplasmic regulator of cell death, Liu emphasized.

However, this is not to say that interferon deficiencies do not have a role. Inborn defects in TLR3-dependent type I interferon immunity in cortical neurons appear to be at the root of forebrain herpes simplex encephalitis caused by uncontrolled virus proliferation and consequent cell death. The researchers discovered a previously unknown genetic relationship between pediatric herpes simplex encephalitis. They also demonstrated how cell death-dependent regulation is an important component of antiviral responses against herpes simplex-1.

“We report an otherwise healthy patient with herpes simplex encephalitis who was compound heterozygous for nonsense and frameshift RIPK3 variants,” Liu said of his team’s findings.

The two mutations detected in the study were nonsense and frameshift mutations in RIPK3. When RIPK3 is functioning normally, it is implicated in the initiation of cell death independent of type I interferon. The combined team discovered that the two mutations resulted in low RIPK3 expression, limiting the immune system from causing cell death—killing infected cells—via apoptosis or necroptosis. Furthermore, in vitro research demonstrated that fibroblasts and neurons produced from the patient could not begin cell death, confirming the team’s findings.

Surprisingly, the RIPK3 deficiency did not seem to make the patient more vulnerable to other types of viral infection. “Inherited RIPK3 deficiency therefore confers a predisposition to herpes simplex encephalitis by impairing the cell death–dependent control of herpes simplex virus-1 in cortical neurons,” Liu concluded.

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