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March 14, 2016

Virus Hijacks MicroRNA to Ensure its Propagation

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    When miR-17 is inhibited (left), the BVDV virus can't replicate and kill its host cells (blue). As a result, fewer viral plaques (cloudy areas) form. [Laboratory of Virology and Infectious Disease of the Rockefeller University/Cell Host & Microbe]

    It is the very simplistic nature of viruses that often makes them notoriously difficult to understand—they have a singular nature, driven by the necessity to replicate and produce more virus. Often considered the ultimate parasite, viruses shed all of their nonessential parts and cram the basics into their diminutive genetic code and packaging, looking to capitalize on any evolutionary advantage that facilitates their propagation goals.

    One recently discovered way some viruses can get a leg up is by subverting the microRNAs (miRNAs) of the host cell. These miRNAs are small stretches of molecular code made by host cells to regulate gene expression. If a virus can co-opt one, it can manipulate its host without having to make its own protein—an invaluable space saver for the viral genome that allows the virus better protection from the host's immune system.     

    While DNA viruses have been shown previously to utilize miRNAs of the cells they infect, as well as produce their own, investigators were surprised when they found last year that hepatitis C (HCV), an RNA virus, not only sequesters a host miRNA but relies upon it. Now, the same team of scientists from Rockefeller University has found evidence that another RNA virus, the bovine viral diarrhea virus (BVDV), which infects cows and other livestock, also depends on miRNAs for infection. 

    "Is HCV an outlier? Is its dependence on miRNA unique?" wondered co-author Joseph Luna, Ph.D., a postdoctoral researcher at Rockefeller University. To see if RNA viruses other than HCV use host miRNAs, the researchers developed a screening method that chemically attaches those miRNAs to their targets.

    "The problem with bioinformatic searches for miRNA targets is that they are small enough to occur every few thousand bases in the transcriptome," explained lead author Troels Scheel, Ph.D., a postdoctoral fellow currently at the University of Copenhagen. "Moreover, computational approaches typically don't know what's expressed in different cell types," and therefore which mRNA sequences they identify as miRNA targets might be physiologically relevant.

    To test if other viruses might use a similar strategy to HCV, the researchers developed a biochemical scan, called CLEAR-CLIP, which identifies real miRNA target sequences by physically linking the miRNA to some of its target mRNA, without the need for any a priori sequence information. The scientists scanned the interactions of 15 RNA viruses with their host miRNAs. Among them were several viruses known to cause human disease, including poliovirus, dengue, and chikungunya virus. Their analysis showed that BVDV, a pestivirus that poses significant trouble in the meat and dairy industries, expressly bound to both miR-17 and another host miRNA called let-7.

    “We used crosslinking immunoprecipitation (CLIP) of the Argonaute (AGO) proteins to characterize strengths and specificities of miRNA interactions in the context of 15 different RNA virus infections, including several clinically relevant pathogens,” the authors wrote. “Notably, replication of pestiviruses, a major threat to milk and meat industries, critically depended on the interaction of cellular miR-17 and let-7 with the viral 3′ UTR. Unlike canonical miRNA interactions, miR-17 and let-7 binding enhanced pestivirus translation and RNA stability. miR-17 sequestration by pestiviruses conferred reduced AGO binding and functional de-repression of cellular miR-17 targets, thereby altering the host transcriptome.”

    The findings from this study were published recently in Cell Host & Microbe in an article entitled “A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration.”

    Typically, miRNAs function through the repression of gene expression; however, in this case, miR-17, stabilizes the BVDV genome. Upon infecting its host, the virus takes control of it by altering the expression of its genes. And since BVDV sops up so much of the host cell's miR-17, it prevents this miRNA from repressing the host genes normally under its control.

    The Rockefeller researchers found they could weaken the replication and production of BVDV by inhibiting its interaction with the miRNA. They say miR-17 might provide a valid target for the development of new drugs to control BVDV.

    “These findings generalize the concept of RNA virus dependence on cellular miRNAs and connect virus-induced miRNA sequestration to host transcriptome regulation,” the authors concluded.

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