Researchers at the Francis Crick Institute have found that a key defense mechanism previously thought to have disappeared in mammals as they evolved is still active in helping to protect mammalian stem cells from RNA viruses such as SARS-CoV-2 and Zika virus. The RNA interference (RNAi) mechanism, mediated by a protein known as Dicer, is active in plants and invertebrates to defend against viruses. The Francis Crick Institute team says the discovery that the mammalian defense system also uses a form of Dicer to protect tissue stem cells from RNA viruses could one day be exploited in the development of new antiviral treatments.

Caetano Reis e Sousa, PhD, group leader of the Immunobiology Laboratory at the Crick, explained, “It’s fascinating to learn how stem cells protect themselves against RNA viruses. The fact this protection is also what plants and invertebrates use suggests it might be something that goes far back in mammalian history, right up to when the evolutionary tree spilt … By learning more about this process, and uncovering the secrets of our immune system we are hoping to open up new possibilities for drug development as we strive to harness our body’s natural ability to fight infection.”

The investigators described their studies using cultured human cells and mouse stem cell-derived organoids, in Science, in a paper titled, “An isoform of Dicer protects mammalian stem cells against multiple RNA viruses.”

On infecting a host, a virus enters cells to replicate, and for most cells in mammals, proteins called interferons (IFNs) are the first line of protection. Stem cells, however, lack the ability to trigger an interferon response, and there has been uncertainty about how these cells protect themselves.

In contrast with mammals, invertebrates and plants don’t have an IFN system, and instead they protect themselves from viral infection by means of RNAi. “Antiviral RNAi starts with the protein Dicer, which recognizes and cleaves double-stranded RNA (dsRNA) produced during RNA virus infection to generate small interfering RNAs (siRNAs),” the authors explained. These then direct the sequence-specific degradation of the viral RNA. But, as the investigators further noted, “whether RNAi also contributes to mammalian antiviral immunity remains controversial.”

For their newly reported study, the scientists analyzed genetic material from mouse stem cells, and found that it contains instructions to build an isoform of Dicer—which they named antiviral Dicer (aviD)—that acts to cut up viral RNA and so prevent RNA viruses from replicating. Interestingly, Reis e Sousa, pointed out, “For some reason, while all mammalian cells possess the innate ability to trigger this process, it seems to only be relied upon by stem cells.”

In laboratory experiments through which the team exposed engineered human cells to SARS-CoV-2, they found that the virus infected three times fewer stem cells when aviD was present in the cells, compared with when aviD was removed. The scientists also grew mini brain organoids from mouse embryonic stem cells and found that, when infected with Zika virus, the organoids with aviD grew more quickly, and less viral material was produced, compared with organoids that lacked the aviD protein. Similarly, when organoids were infected with SARS-CoV-2, there were fewer infected stem cells in the organoids with aviD. In summary, the authors wrote, “We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses—including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—by dicing viral double-stranded RNA to orchestrate antiviral RNAi.”

Co-author Enzo Poirier, PhD, a postdoc in the Immunobiology Laboratory at the Crick, noted, “Why stem cells use this different mechanism of defense remains a mystery. It might be that the interferon process would cause too much harm to stem cells, so mammals, including humans, have evolved to shield these precious cells from this damage.” As the authors noted, “Our results show that the Dicer gene can generate an alternative transcript that encodes aviD, a truncated Dicer that helps protect mouse and human stem cells against RNA virus infection and compensates in part for stem cell hyporesponsiveness to innate IFNs.”

The researchers plan to continue this work, creating a mouse model which will allow them to further study the effects and importance of aviD in mammalian stem cells. They concluded, “Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.” Poirier continued, “There is still a lot of uncertainty about how these cells are protected from viruses, which we’re excited to explore further.”

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