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Columbia Team Reports on Inherited Small RNA-Based Immune Response in C. elegans


By Doug Macron

Researchers from Columbia University Medical Center this month reported new data showing that C. elegans exposed to a virus can pass an acquired small RNA-based immune response to their progeny in a non-Mendelian manner.

According to the findings, the worms “memorize” a viral-expression episode in the form of virus-derived, small interfering RNAs, or viRNAs, that are “transmitted through many ensuing generations in the absence of the genetic template, and even in the absence of ... functional small RNA-generating machinery.

“These inherited viRNA molecules are capable of protecting ensuing generations from the virus by silencing the expression of the viral genome,” a discovery that supports the “Lamarckian concept of inheritance of an acquired trait,” the team wrote in the Dec. 9 issue of Cell.

While C. elegans are capable of fighting off virtually all viral infection using a potent RNAi-based process, a wild strain of the worm was recently discovered to be infected with a new single-stranded RNA virus from the nodavirus family due to an inability to mount an effective RNAi response, the researchers wrote. “In contrast, laboratory strains with an intact RNAi response ... could not be efficiently infected with this RNA virus.

“These observations indicate that the RNAi pathway attacks dsRNA intermediates that single-strand RNA viruses … generate during replication” by processing the viral dsRNA trigger into viRNAs. These, in turn, confer viral immunity via Argonaute-dependent RNAi.

Since the ability to respond to specific viruses with targeted viRNAs is an acquired trait, the team aimed to see whether it is also transmitted transgenerationally.

“I knew about the link between RNAi and anti-viral defense,” Oded Rechavi, lead author of the Cell paper, told Gene Silencing News this week. “I thought that if worms are exposed to and can resist viruses, maybe the protections they establish by creating small viral RNAs … are transmitted to the next generation as a sort of antiviral vaccine.”

The process, he said, would be analogous to a bacterial phenomenon in which DNA viruses are processed by bacteria into fragments, he explained. “When they do, the DNA fragments are integrated … [and] become part of the bacterial genome … [getting] passed onto the next generation.”

To test this hypothesis, the CUMC team used a C. elegans model that supports autonomous replication of another nodavirus, Flock House, which fluoresces when it is translated.

“In wild-type worms, because the RNAi machinery is very efficient, you never get GFP expression because the virus is continuously chopped up by the immune system,” Rechavi said. “We crossed such worms to RNAi mutants deficient … in their ability to establish a de novo RNAi response.”

When subsequent generations of these worms were challenged with Flock House, they proved immune to the virus despite having no RNAi abilities, suggesting that they inherited the protection “in an extra-chromosomal way, independently of DNA,” he said.

RNAi-deficient worms whose parents never encountered Flock House, meantime, were efficiently infected by the virus.

Rechavi said that he and his colleagues in the lab of Oliver Hobert plan to next see if other C. elegans traits are inherited via small RNAs.

“One may speculate that the recently described inheritance of an olfactory memory or the transgenerational inheritance of longevity traits could also be the result of inherited small RNA molecules,” the CUMC team wrote in Cell.

Rechavi said that another area of particular interest is to see if starvation-induced responses are passed along from parent to progeny, a line of research inspired by anecdotal evidence from the Dutch famine of 1944.

During the Nazi occupation of the Netherlands, many Dutch people faced starvation, he explained. “Later it was found that … the children and grandchildren of starved people had different metabolisms and were smaller and thinner. This is an interesting angle to pursue in worms, where you can do the proper controls and try to understand the mechanism,” he said.

Rechavi also hopes that the findings reported in Cell will translate to other organisms.

“It seems that everything they find in worms later translates to higher organisms,” he said.

“It's true that worms have additional components of the RNAi machinery that higher organisms don't … however, higher organisms have mechanisms that C. elegans lack that might compensate for that.

“Worms have no DNA methylation, [for instance, while] higher organisms do,” he said. “It is now known that small RNAs can guide methylation from DNA in several organisms. It could be that, to have a lasting imprint of an RNA response, higher organism might recruit the mechanism of DNA methylation.”

Given that Hobert's lab focuses primarily on C. elegans, however, such research will be left to other investigators, he noted.

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