Ancient Viral DNA Helps Mouse Brains Fight Infection

Amazing stuff!

Our symbiosis with viruses is probably much deeper and much more involved!

30 years of painstaking detective work!

 

"Remnants of ancient viral DNA are still active in the genomes of animals alive today. At some point in evolutionary history, many of these so-called endogenous retroviruses inserted themselves into the DNA of their host, and their genetic code has been present ever since. Studies have found that this leftover DNA still serves crucial roles unique to mammals.

In a study ... scientists say they’ve characterized two retrovirus-derived genes that fight infections in the brains of mammals that give birth to live young, a group known as eutherians.  ...
Study coauthor Tomoko Kaneko-Ishino, a geneticist at Tokai University in Japan, says it took her more than 30 years to uncover the function of two virus-derived genes. ...
Over the next decade, Kaneko-Ishino’s team studied the function of RTL genes, and in experiments that would begin the new study, she compared the genomes of animals in various phylogenetic groups and found that two of these genes, RTL5 and RTL6, were evolutionarily conserved among eutherians but not in other mammals. ...
for 15 years, as she and her team studied the animals, they failed to pinpoint the purpose of the genes or their proteins, despite trying various “gold standard” techniques ...

She unearthed another clue three years ago, when her team used genetic engineering to attach fluorescent proteins to the ends of the RTL proteins in mice and saw that RTL5 and RTL6 were localized in immune cells in the brain called microglia. ...

team began looking for ways to enhance the signal, and, because only immune cells expressed the proteins, they thought that infection might do the trick. They began injecting fluorescently labeled toxins, including the bacterial toxin lipopolysaccharide (LPS) as well as nonmethylated DNA and double-strand RNA, both common viral warning signals, directly into the mice’s brains.

After an LPS injection, the researchers saw a sharp increase in the amount of RTL6 protein in the brain at the injection site. They also found that LPS lingered longer in the brains of RTL6 knockout mice than their normal counterparts, while RTL5 knockout mice were slower at clearing double-strand RNA. ...
the first evidence of virally derived, eutherian-specific genes involved in immunity. “It is quite interesting that mammals reuse virus-derived genes not only for [the] innate immune system but also in formation of [the] placenta,” ..."

From the abstract:

"Retrotransposon Gag-like 5 [RTL5, also known as sushi-ichi-related retrotransposon homolog 8 (SIRH8)] and RTL6 (also known as SIRH3) are eutherian-specific genes presumably derived from a retrovirus and phylogenetically related to each other. They, respectively, encode a strongly acidic and extremely basic protein, and are well conserved among the eutherians. Here, we report that RTL5 and RTL6 are microglial genes with roles in the front line of innate brain immune response. Venus and mCherry knock-in mice exhibited expression of RTL5-mCherry and RTL6-Venus fusion proteins in microglia and appeared as extracellular dots and granules in the central nervous system. These proteins display a rapid response to pathogens such as lipopolysaccharide (LPS), double-stranded (ds) RNA analog and non-methylated CpG DNA, acting both cooperatively and/or independently. ..."

Ancient Viral DNA Helps Mouse Brains Fight Infection | The Scientist Magazine® Mammals that give birth to live young may have evolved to make use of the remnants of viruses in their genomes to ward off pathogens, a study suggests. 

Retrovirus-derived RTL5 and RTL6 genes are novel constituents of the innate immune system in the eutherian brain (open access)