Findings could signal paradigm shift in understanding of host response to viral infection
Scientists have demonstrated for the first time that a certain class of RNA (known as long non-protein-coding RNA [lncRNA]) are involved in the host response to viral infection. These findings, published today in the online journal mBio-, could greatly change the way scientists look at the body's response to viral infection.
"To our knowledge, our study is the first to use comprehensive deep-sequencing technology to clearly demonstrate that lncRNAs are involved in the host response to viral infection and innate immunity," says Michael Katze of the University of Washington, and STRIDE (Center for Systems and Translational Research on Infectious Disease) in Seattle, a lead researcher on the study.
RNA molecules are transcribed from the DNA and help translate the genetic code. They often serve as templates for building compounds the body needs to function including proteins.
Most studies of how animals' cells respond to viral infections focus only on protein-coding genes, which assemble germ-fighting or inflammation-inducing proteins used by the immune system. However there is growing evidence that thousands of RNAs are transcribed that do not code for proteins.
"The relevance of lncRNAs to viral infections has not been systematically studied, in part because these ncRNAs have not been easily accessible with typically available technologies," says Katze. "With the advent of next-generation sequencing technologies, whole transcriptome analysis of the host response, including ncRNAs, is now possible."
The library of RNA transcripts inside of a cell is called its transcriptome and is a reflection of gene activity. Many different RNAs can be read from a single gene. Therefore a transcriptome contains much more complex instructions than would seem possible from the DNA code. Unlike the genome, the transcriptome varies in different types of cells in the body and in accordance with ever- changing conditions inside and outside the cell.
Katze and his research team used highly advanced technologies, such as next generation sequencing (NGS), to perform a whole transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza infection in four strains of mice, some more susceptible to the viruses than others. Using this deep-sequencing technology, the researchers analyzed whole transcriptomes in cells from infected lung samples collected from the mice.
The researchers observed that virus infection triggered activity in about 500 lncRNAs transcribed from known locations on the genome and about 1,000 from previously unspecified genomic regions.. They were also interested to discover, through studies of subsets of the lncRNAs and genomic regions, that most of these were similarly regulated in response influenza virus infection. This profile contained unique "signatures" of lncRNA activity and these signatures were associated with lethal infection.
"These findings represent the first discovery of the widespread differential expression of long ncRNAs in response to virus infection and suggest that ncRNAs are involved in regulating the host response, including innate immunity," says Katze. "In the future, it is likely that a detailed knowledge of ncRNA regulation and function will be necessary for a full understanding of viral pathogenesis."
This project was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.