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Genetic Mutation Linked to Viral Brain Infections

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Posted May 11, 2018

A group of scientists including a Northwestern Medicine investigator has discovered a link between a genetic mutation and a rare condition in which a common virus enters the brainstem and causes brain swelling, according to the study published in Cell.

Gregory Smith, PhD, professor of Microbiology-Immunology, was a co-author of the paper, which found mutations in a gene called DBR1 caused brainstem cells to be more susceptible to infection by herpes simplex virus 1 (HSV1), findings that shed light on the mysterious origin of viral infections of the central nervous system, according to the study.

Gregory Smith, PhD, professor of Microbiology-Immunology, was a co-author of a paper published in Cell. Credit: Northwestern University

HSV1 is a common inhabitant of the nervous system, but in most people it is restricted to the peripheral nervous system from which it sometimes remerges to cause cold sores. And yet, in rare cases, the virus spreads beyond the peripheral nerves and traffics along the neural circuitry into the brain.

When they occur, viral brain infections can cause encephalitis — severe swelling of the brain — and often strike otherwise healthy children. Lack of forewarning and little knowledge about who is at risk result in high mortality rates, according to the study.

To investigate a possible genetic cause, Smith and his collaborators evaluated seven patients with confirmed or suspected brainstem viral encephalitis caused by HSV1, finding DBR1 mutations in five of the encephalitis patients but not in any of their 29 healthy relatives, who were also tested.

According to the study, presence of these DBR1 mutations was also correlated with accumulation of lariats — discarded byproducts of RNA splicing — that spiked during HSV1 infection, and DBR1 was highly expressed in the brainstem and spinal cord.

In laboratory models using yeast, these phenomena were reversed by replacing the mutated DRB1 with the standard DRB1, suggesting the mutated DRB1 genotype caused the susceptibility to viral infection. This study marks the first time a genetic cause for brainstem viral encephalitis has been identified, according to the study.

Furthermore, the findings suggest the abundance of lariats has an impact on immune response in brainstem cells, lending weight to the theory that single-gene mutations can cause cell-specific deficits in immune response.

Because DBR1 is highly expressed in the brainstem, it disrupted immunity in a small, specific set of cells, which suggests that repairing these cell-specific mechanisms could be critical for controlling viral illnesses such as brainstem viral encephalitis, according to the study.

However, further studies are required to fully understand the mechanisms by which DBR1 affects antiviral defense in brainstem cells before a therapy could be developed, according to the authors.

Source: Northwestern University

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