Scientists have discovered the important role of microglia cells in protecting a mouse brain’s central nervous system from viral infections that entered the brain through the nose.

Despite entering the body through the nose — which gives a pathogen a direct route to the brain via olfactory neurons — many viruses rarely manage to cause fatal damage in the brain. Researchers at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health wanted to figure out why that’s the case. In a new study published recently in Science Immunology, they infected mice with a respiratory virus called vesicular stomatitis virus to track the immune system’s response.

“You’re not trying to find out why the system [is] broken — the system usually works,” said Ashley Moseman, an assistant professor at Duke University School of Medicine and a co-author of the study. Past studies have shown that the brain can expel a virus without killing many of its own finite number of neurons, but they wanted to pinpoint how that process occurs.

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Their research found an unlikely hero: microglia. Microglial cells in the brain are not infected themselves by invading viruses. Rather, the study found that microglia actually find antigens — the toxins a virus gives off in the brain — and present them to the T cells that need to kill them.

“We don’t want T cells to go into the brain and kill things that they aren’t supposed to kill,” said Moseman. So, he said, the microglia “acquire antigen in a way that allows them to present antigen in the area, but avoid some of these tricky situations.”

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The team observed the process between microglia and T cells by using a virus that would leave a stain to show everywhere it’s been, allowing them to see all the cells that survived infection. They used microscopes to observe the live cells interacting — red-colored T cells flashed green when they came in contact with microglia and killed the antigen.

Later in the study, the team infected mice again, this time after reducing microglia in their brain. Under the microscope, they observed that T cells were less likely to recognize antigens when microglia were fewer. The mice also had reduced survival rates with lower counts of microglia, demonstrating how critical a role this cell type plays in the brain’s protection.

The researchers do not know how microglia are affected after a T cell kills the antigen. The encounter might kill microglia, too, but the stakes are lower, according to Moseman. Microglia can regenerate in ways that central nervous system neurons cannot. But it’s still an important question to ask, Moseman said, because what happens to microglia could have implications about how in control they are of T cells during this process.

The research has no immediate clinical implications, but scientists hope it will spark more study of how the brain protects itself and how those natural defenses could be enhanced. Many researchers are particularly interested in a possible connection to SARS-CoV-2, the virus that leads to Covid-19.

Loss of smell and taste are major symptoms of Covid-19, demonstrating a potential interference in the brain when infected. But experts said it’s also still unclear whether SARS-CoV-2 can enter the brain through neurons in the nose and, if so, how that might be prevented.

The findings are an important step toward researching possible interventions for when the brain’s defense system doesn’t work, said Ari Waisman, chair and professor of immunology at University Medical Center of the Johannes Gutenberg University of Mainz, who wasn’t involved in the research. He said there is now a question of whether the mechanism this study revealed, which occurs after the virus has infected the central nervous system, could be manipulated to happen earlier to protect the brain from other pathogen invasions.

“Microglia has a lot of roles in antiviral infection that were not appreciated before,” said Waisman.

While the study sheds light on the brain’s successful self-defense, it’s important to emphasize that this process occurs when the virus is already in the body and in the brain, Moseman said.

“If you’re trying to prevent invasion in the first place, you should consider the surface that is going to be invaded,” he said. “Once you get infected, you have to deal with the consequences one way or the other.”

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