Researchers from the University of New South Wales (UNSW) Sydney report they have discovered that a particular transposable element in the genome has an effect on the immune response to virus infection. The researchers’ findings demonstrate how the immune system is regulated, and have potential implications for the treatment of virus infections that can lead to an overactive immune response.
The findings are published in the journal Nature in a paper titled, “The retroelement Lx9 puts a brake on the immune response to virus infection.”
“The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago,” wrote the researchers. “However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes.”
“It shows very clearly that a transposable element can control the immune system to favor host survival following virus infection and it’s probably been selected to remain in the genome for this very reason,” said senior author Cecile King, PhD, associate professor from UNSW Science’s School of Biotechnology & Biomolecular Sciences.
King explained that to really understand the jumping genes’ function, researchers needed to observe what happens when they remove one of these transposable elements from an animal.
“That has been difficult because transposable elements are repetitive, and their ability to multiply across the genome has been one reason why they’re so prominent in terms of the content of our genome,” she said.
“When you’re trying to knock one out, you often actually target a whole group of them across the genome on different chromosomes, so it’s been a little bit tricky to do.”
The team attempted to analyze the effect of transposable elements on the immune system.
“When it’s a virus infection, the majority of those (active) genes are going to be immune response genes. “Then we can ask questions about what transposable elements actually do in terms of their function and their effect on a complex biological system such as the immune system.”
They selected an ancient transposable element. This particular transposable element is located near one of the most highly expressed genes following virus infection, in the Schlafen gene family. There are 10 Schlafen genes in mice and seven in humans and they are critically important as they encourage cell proliferation in response to viruses and inhibit virus replication. After knocking out one of the transposable elements, called Lx9c11, from mice, the researchers infected the animals with Coxsackievirus B4, a virus that largely affects the pancreas and some other tissues. But instead of usually clearing the virus, the mice who had lost the Lx9c11 element died.
The researchers discovered the Lx9c11 deficient mice had an exaggerated immune response, similar to what is rarely experienced by influenza patients and more commonly experienced by people with severe COVID-19. “We found that they had increased damage to the pancreas; infiltration of cells into the lung; activation of immune cell subsets; dysregulated blood glucose levels; weight loss; and lethality. And the data indicated that the lethality was host induced,” King said.
“We think that this is going to be a commonly observed phenomenon, that we’re going to learn how transposable elements similar to Lx9c11, control the expression of gene families throughout the genome,” King added. “Are transposable elements druggable? I don’t think it’s impossible, because antisense technology (a tool for controlling gene expression in a cell) has been FDA-approved. For example, if you were to block the expression of Lx9c11, you would actually boost the immune response quite markedly, but we need a lot more research to figure out how that could work.”