CNS infections: interferon gamma could play a role in blood–brain barrier breakdown

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A new study has implicated the cytokine interferon gamma as a major contributor of blood–brain barrier breakdown in central nervous system (CNS) infections.

Previous studies have demonstrated a loss in the integrity of the blood–brain barrier during CNS infection, and interferon type 1 and type 2 have both been implicated. However, the mechanisms at the cellular and molecular level have been poorly understood.

This study, published recently in mBio, used an experimental viral encephalitis mouse model where the mice were infected with reovirus to study blood–brain barrier breakdown. The researchers also carried out in vitro experiments using cultured brain endothelial cells.

The team discovered that blood–brain barrier breakdown occurs late in the course of the disease. Principal study investigator, Julie Siegenthaler (University of Colorado, CO, USA) explained: “Disease progression happens over about 10 days. We see the blood brain barrier breakdown happening in the last 6–7 days after infection, after seeing evidence that the virus is being replicated and after seeing evidence that there is an inflammatory response.”

The researchers also observed that infection upregulated interferon gamma, and that endothelial cells in the blood–brain barrier responded to interferon gamma, losing their integrity as a result of Rho kinase-mediated cytoskeletal contractions leading to loss of junctions and cell–cell separation.

Siegenthaler commented: “Infection with reovirus causes a change in the proteins that regulate the cytoskeleton. It causes an overactivation of the cytoskeleton, causing the cells to pull apart from each other, which has not been shown before.”

It was also observed that by blocking interferon gamma signalling many of the disruptions could be restored. The team suggest more research is needed to see if flaviviruses impact the blood–brain barrier in the same way as reovirus, and whether the findings are applicable to humans. However, the work could lead to therapeutics.

Author, Kenneth Tyler (University of Colorado), concluded: “Interferon was one of the things that was causing not only a loss of pericytes, support cells, but a disruption of the connections that are usually pretty tight between endothelial cells in the blood brain barrier called tight junctions and adherens junctions.”

“Manipulating the blood brain barrier in combination with antiviral therapies may lead to better outcomes.”

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Source: Bonney S, Seitz S, Ryan CA et al. Gamma interferon alters junctional integrity via rho kinase, resulting in blood-brain barrier leakage in experimental viral encephalitis. mBio. doi:10.1128/mBio.01675-19 (2019); www.asm.org/Press-Releases/2019/August-1/Study-Explores-Blood-Brain-Barrier-Leakage-in-CNS


What is the blood–brain barrier?

The blood–brain barrier is a highly selective, semipermeable membrane separating the blood from the cerebrospinal fluid. This is a protective element preventing the passage of cells, particles and large molecules.

What is interferon gamma?

Interferon gamma is a cytokine that is a member of that type 2 class of interferons. It plays a critical role in innate and adaptive immunity as the primary activator of macrophages.

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