In the ongoing arms race between pathogenic viruses and the cells they infect, each side needs every advantage it can get. One way wily viruses can get a leg up is by subverting the micro-RNA (miRNA) of their host.

The miRNAs are small stretches of RNA 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. This strategy saves valuable space in the viral genome and allows the virus to better hide from the host's immune system, according to an announcement from Rockefeller University.

DNA viruses are known to utilize the miRNA of the cells they infect; they even produce their own. Last year, Rockefeller scientists were surprised to discover that hepatitis C, a virus that contains RNA rather than DNA, not only sequesters a host miRNA but relies on it.

Now, the same team — including researchers in the laboratories of Charles M. Rice, the Maurice R. & Corinne P. Greenberg professor and head of the Laboratory of Virology & Infectious Disease, and Robert B. Darnell, the Robert & Harriet Heilbrunn professor and head of the Laboratory of Molecular Neuro-oncology — has found evidence that another RNA virus — bovine viral diarrhea (BVD) virus, which infects cows and other livestock — also depends on miRNA for infection. Their results are reported in Cell Host & Microbe.

A new surveying technique

To see if RNA viruses other than hepatitis C use host miRNA, 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," said study first author Troels Scheel, now at the University of Copenhagen in Denmark. "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.

In contrast, a biochemical scan called CLEAR-CLIP — developed in the labs of Darnell and Rice — 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.

Joseph Luna, a post-doctoral researcher in Rice's lab, wondered if hepatitis C virus is "an outlier" and whether its "dependence on miRNA (is) unique." To find out, he and his colleagues used CLEAR-CLIP to analyze the interactions of 15 RNA viruses with their host miRNA. Among them were several viruses known to cause human disease, including poliovirus, dengue and chikungunya virus.

Their analysis showed that BVD virus, a pestivirus that poses major trouble in the meat and dairy industries, specifically bound to both miR-17 and another host miRNA called let-7.

Usually, miRNA functions by repressing the expression of genes or their translation into protein. However, in this case, miR-17 stabilizes the BVD viral genome, just as miR-122 does for hepatitis C virus. Upon infecting its host, the virus takes control of it by altering the expression of its genes, and since the BVD virus 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 researchers explained.

The scientists found that they could weaken the replication and production of the virus by inhibiting its interaction with the miRNA. They said miR-17 might provide an effective target for the development of new drugs to control BVD.

In the report, the researchers speculate that dependence on host miRNA might be a general phenomenon in pestivirus replication, although they are not yet sure what biological purpose it could serve. Regardless of its function, this interaction between pestiviruses and miRNA may provide a ripe target for antiviral therapies since viral replication depends on it.