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Oct 11, 2013

iRNA’s Antiviral Path in Mammals Not Abandoned, Just Less Traveled

  • Long doubted, the existence of antiviral RNAi in mammals has finally been confirmed. Two companion studies, published October 11 in Science, have found convincing evidence of antiviral iRNA in cultured mouse embryonic stem cells and in the tissues of young mice.

    RNAi, or interference RNA, was already known to exist in mammals, but most researchers believed that its functions were limited to gene regulation, and did not extend to antiviral immunity. Some researchers, however, wondered why RNAi, which mounts powerful defenses against viruses in plants and invertebrates, appeared to lack a corresponding antiviral function in mammals.

    The key, it turned out, is that viruses have found a way to use proteins to suppress mammalian RNAi defenses. An expert in such proteins, Shou-Wei Ding, Ph.D., a professor of microbiology at the University of California, Riverside, had identified them first in plants, then in nematodes and fruit flies. One of the proteins, as Dr. Ding was aware, was associated with two closely related viruses, the Flock house virus, which infects insects, and the Nodamura virus, which infects mice.

    This realization set the stage for the experiments Dr. Ding’s study, “RNA Interference Functions as an Antiviral Immunity Mechanism in Mammals.” This study describes how removing a protein called B2, an RNAi antagonist encoded by Nodamura virus, allowed infected mice to produce huge armies of virus-attacking siRNAs. Infected mice in which B2 remained to suppress innate immunity all died.

    “If RNAi remains as an effective antiviral defense in plants, insects, and nematodes after their independent evolution for hundred millions of years,” Dr. Ding had asked, “why would it stop working in mice?” Joining Dr. Ding’s team in exploring this question, an independent group, led by Oliver Voinnet, Ph.D., professor for RNA biology at EH Zurich, published a related study, “Antiviral RNA Interference in Mammalian Cells.”

    These researchers infected mouse embryonic stem cells with two viruses, the encephalomyocarditis virus and the Nodamura virus. Subsequently, they were able to detect short RNA molecules of about 22 nucleotides in length within the cells. The sequence of these RNA clearly corresponded to the viral genome and they displayed all the characteristics of the main effector molecules of RNAi called the small interfering or siRNAs. This provided evidence that the virus infection had activated the RNAi machinery of mammalian cells.

    To provide further evidence for a function of RNAi in mammalian antiviral immunity, the researchers modified the Nodamura virus genetically to eliminate what they thought was its suppression mechanism against RNAi. Subsequently, they infected mouse stem cells with the modified virus and observed that the cells could fend off this virus much better than the original Nodamura virus.

    Dr. Voinnet suggests that the antiviral role of mRNAi may have been overlooked in mammals not only because viruses employ effective suppression mechanisms, but also because innate immunity in differentiated cells is dominated by the interferon response.

    The insights produced by the two studies point to interesting questions for additional research. For example, what role does differentiation play? Is it possible that some differentiated cell types, but not others, are capable of mounting antiviral RNAi responses? Also, will investigation of the RNAi antiviral function lead to new vaccines for human pathogens?

    “Maybe this is what we have been missing in knowing how humans combat viral infections,” said Dr. Ding. “There are many different antiviral mechanisms in our bodies, but maybe RNAi functions as the most important antiviral defense mechanism. Maybe this is the one that really matters.”



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