A group of small, freshwater animals protect themselves from infections using antibiotic recipes “stolen” from bacteria, according to new research by a team from the University of Oxford, the University of Stirling and the Marine Biological Laboratory (MBL), Woods Hole.
The team found that when these bdelloid rotifers are exposed to fungal infection, they switch on hundreds of genes that they acquired from bacteria and other microbes. Some of these genes produce resistance weapons, such as antibiotics and other antimicrobial agents, in the rotifers.
“When we translated the DNA code to see what the stolen genes were doing, we had a surprise,” said lead Chris Wilson, PhD, at the University of Oxford. “The main genes were instructions for chemicals that we didn’t think animals could make—they looked like recipes for antibiotics.”
The scientists think that rotifers could give important clues in the hunt for drugs to treat human infections caused by bacteria or fungi. “The recipes the rotifers are using look different from known genes in microbes,” said Reuben Nowell, PhD, at the University of Stirling. “They’re just as long and complicated, but parts of the DNA code have changed. We think the recipe has been altered by a process of evolution to make new and different chemicals in the rotifers. That’s exciting because it might suggest ideas for future medicines.”
Wilson, Nowell and colleagues reported on their findings in Nature Communications, in a paper titled “Bdelloid rotifers deploy horizontally acquired biosynthetic genes against a fungal pathogen.” In their paper the team concluded “… “our results raise the intriguing possibility of discovering new antimicrobial compounds in bdelloids.”
“Bdelloid rotifers are a class of microscopic, filter-feeding invertebrates that live in freshwater and limnoterrestrial habitats worldwide,” the authors wrote. The tiny creatures— the name means ‘crawling wheel-animals’—have a head, mouth, gut, muscles and nerves like other animals, though they are smaller than a hair’s width.
Prior research found that rotifers have been picking up DNA from their surroundings for millions of years. “… repeated studies have demonstrated that bdelloid genomes encode extraordinarily high proportions of genes acquired horizontally from nonmetazoan taxa,” the investigators stated. No other animals are known to “steal” genes from microbes on such a large scale, the team suggested. “Approximately 10% of genes appear to have been captured from bacteria, fungi, plants and other sources, rather than sharing recent common ancestry with metazoan orthologs.”
The new study is the first to discover that the organisms use these genes against diseases. For their study the investigators used RNA-seq technology to identify genes that were differentially expressed when the bdelloid rotifers were attacked by a natural fungal pathogen. The team compared data from two different species of rotifer, one that was susceptible to the pathogen, and one that was more resistant. The scientists also compared their results with RNA-seq data from bdelloid rotifers were exposed to desiccation.
The results showed that following challenge with the fungal pathogen, horizontally acquired genes in the organisms were over twice as likely to be upregulated as other genes “ … a stronger enrichment than observed for abiotic stressors,” the team also pointed out.
Co-author David Mark Welch, PhD, senior scientist and director of the Josephine Bay Paul Center at the Marine Biological Laboratory, further commented, “These complex genes— some of which aren’t found in any other animals—were acquired from bacteria but have undergone evolution in rotifers. This raises the potential that rotifers are producing novel antimicrobials that may be less toxic to animals, including humans, than those we develop from bacteria and fungi.
Antibiotics are essential to modern healthcare, but most of them were not invented by scientists. Instead, they are produced naturally by fungi and bacteria in the wild, and humans can make artificial versions to use as medicine. The new study suggests that rotifers might be doing something similar.
“These strange little animals have copied the DNA that tells microbes how to make antibiotics,” explained Wilson. “We watched them using one of these genes against a disease caused by a fungus, and the animals that survived the infection were producing 10 times more of the chemical recipe than the ones that died, indicating that it helps to suppress the disease.”
The new results, the authors noted, “… suggest that bdelloid rotifers have spent millions of years ‘bioprospecting’ for antimicrobial synthesis machinery across multiple domains of life, and adapting it for large-scale expression in animal cells to defend against fungi or bacteria,” the investigators noted. “If so, investigations of the secondary metabolome of bdelloid rotifers may be of considerable interest in the search for novel antimicrobial agents to treat animal infections.”
Antibiotics are becoming less effective because of the increasing problem of antimicrobial resistance. The World Health Organization recently sounded the alarm, warning in a June report of the “pressing need” to develop new antibiotics to counter the threat of resistance.
The genes the rotifers acquired from bacteria encode an unusual class of enzymes that assemble amino acids into small molecules called non-ribosomal peptides. “Among hundreds of upregulated genes, the most markedly overrepresented were clusters resembling bacterial polyketide and nonribosomal peptide synthetases that produce antibiotics,” the authors stated. Upregulation of these clusters was nearly ten times stronger in the pathogen-resistant rotifer species than in the susceptible species.
“The next phase of this research should involve identification of multiple non-ribosomally synthesized peptides produced by bdelloid rotifers, and establishment of the conditions upon which the synthesis of these compounds can be induced,” said study co-author Irina Arkhipova, PhD, senior scientist at the Marine Biological Laboratory.
One problem with developing new drugs is that many antibiotic chemicals made by bacteria and fungi are toxic or have side-effects in animals. As the team noted, “Prospecting for antimicrobials in nature is largely limited to bacteria and fungi. Among various barriers to developing successful products is the high probability that a compound will be toxic to animal cells and, therefore, fail early stages of testing.” If rotifers are already making similar chemicals in their own cells, they could lead the way to drugs that are safer to use in other animals, including people.
A big question is why rotifers are the only animals that borrow these useful genes from microbes at such high rates. “We think it might be linked with another strange fact about these rotifers,” said Tim Barraclough, PhD, a study co-author from the University of Oxford. “Unlike other animals, we never see male rotifers. Rotifer mothers lay eggs that hatch into genetic copies of themselves, without needing sex or fertilization.”
According to one theory, animals that copy themselves like this can become so similar that it starts to be unhealthy. “If one catches a disease, so will the rest,” explained Barraclough. Because bdelloid rotifers don’t have sex, which allows the parental genes to recombine in beneficial ways, the rotifer mother’s genome is directly transferred to her offspring without introducing any new variation.
“If rotifers don’t find a way to change their genes, they could go extinct. This might help explain why these rotifers have borrowed so many genes from other places, especially anything that helps them cope with infections,” said Barraclough. The authors further stated, “An association between horizontally acquired genes and bdelloid defence against pathogens is consistent with a range of evidence that genetic transfer may be evolutionarily favoured in part to address biotic conflict, and with the specific hypothesis that diseases pose a challenge for lineages where sex is rare or absent, with special measures required to keep up in the long term.”
Nowell thinks there is much more to learn from rotifers and their stolen DNA “The rotifers were using hundreds of genes that aren’t seen in other animals. The antibiotic recipes are exciting, and some other genes even look like they’ve been taken from plants. The findings are part of a growing story about how and why genes get moved between different kinds of life,” he said.
