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Ancient retrovirus genes play crucial role in brain’s innate immune response

Written by Lauren Robertson, Science Writer.

New research has uncovered the role of two specific mouse genes – leftover by a viral infection many millions of years ago – in protecting our brains against potential new infections. The study, published in the journal Development, could further our understanding of the mechanisms behind human evolution.

Not so bad after all…

After the last couple of COVID-filled years, you’d be excused for thinking only of the negative short-term (and potentially long-term) impacts of viral infections on our health. But, as it turns out, viruses could also play a crucial role in shaping our evolution and helping us to stay healthy.

Scientists are already aware that retrovirus genes, left behind by an infection millions of years ago, are capable of being incorporated into our DNA and passed down through generations. The retrotransposon Gag-like 5 and 6 (Rtl5/Rtl6) genes are carried by almost all mammals and have been preserved in the mammalian genome for at least 120 million years – but their exact function has yet to be understood. Therefore, Fumitoshi Ishino (Professor of Molecular Biology at Tokyo Medical and Dental University, Japan) and Tomoko Kaneko-Ishino (Professor of Molecular Biology at the Tokai University, in Kanagawa, Japan) decided to look more closely at how these genes were working in mice.

First, they investigated the role of the genes’ corresponding proteins in a bid to figure out where exactly the genes were active. Interestingly, Rtl5 and Rtl6 were found to be switched on in microglia cells, which are known as the “first responders” to infection in the brain. These cells are involved in removing pathogens from the brain via a variety of Toll-like receptors.

“We never expected that Rtl6 and Rtl5 would function in microglia when we started this work 15 years ago, and even when we knew that Rtl6 was a microglial gene we didn’t understand its significance,” said Kaneko-Ishino. “Our ‘eureka moment’ came during a dissection when Dr Ishino was carefully removing a mouse brain. We realised that if instead we damaged the brain, we could activate RTL6.”

A deeper understanding of the brain’s innate immune system

After this “eureka moment,” the researchers decided to set up fake infections in mouse brains to test how microglia would respond to bacterial or viral infection. They found that microglia containing RLT5 proteins responded to viruses, while RTL6 microglia responded to bacteria. The proteins also seemed to function by trapping invading pathogens and preventing them from spreading.

Figure 1: The RTL6 proteins, shown in green, guard the mouse brain capillaries (the branch-like structures in black) against ‘infection’ by clustering around the magenta-coloured bacterial mimic. Image courtesy of Tomoko Kaneko-Ishino

To test their theory further, the team then removed the Rtl6 and Rtl5 genes and found the mice could no longer eliminate the fake infections. This is the first example of viral-derived genes being re-purposed to protect mammalian brains against infection.

Alongside their research, the team also developed a theory that genes such as these might be first tested in extra-embryonic tissues before being functionally selected for in a developing foetus and carried throughout evolution. They suggest that these extra-embryonic tissues, like the placenta, might play a crucial role as the origin site of retrovirus-derived genes, warranting further investigation in the future.

According to Kaneko-Ishino, “virus-acquired genes are essential parts of our genome, playing various – but essential – roles in mammalian and human development. We think it is possible to extend this idea to primate- and human-specific acquired genes from retroviruses to help us understand human evolution.”

More on these topics

Brain / Evolution / Immune System / Virus