New Player in Innate Immunity? Class of Biomolecules Triggered in Response to Respiratory Virus Infection
ScienceDaily (Nov. 7, 2010) — For the first time, scientists have discovered that a poorly understood class of RNA produced in a mammal's cells during a respiratory virus attack may affect the outcome of the infection. Their findings are reported in mBio, a journal of the American Society for Microbiology.
RNA (ribonucleic acid) contains information transcribed from the cell's instruction manual, its DNA. The best known of these RNAs translate sections of DNA code into building blocks for proteins.
Most studies of how animals' cells respond to virus infection typically look at protein-coding genes, which produce germ-fighting or inflammation-producing substances. However, mammalian cells also transcribe thousands of other RNAs that don't code for proteins.
"The role of most of these non-protein-coding RNAs remains an enigma," noted lead author of the study Dr. Xinxia Peng, a computational research scientist in the Department of Microbiology, University of Washington (UW) School of Medicine in Seattle. Dr. Michael Katze, UW professor of microbiology, directed the project. Katze heads the Center for Systems and Translational Research on Infectious Disease (STRIDE).
"Some attention," Katze said, "has been given to small RNAs, like microRNAs, in host-virus interactions, but now it's becoming apparent that many long-non-protein coding RNAs -- bigger than 200 nucleotides -- are also biologically important."
Researchers are learning that long non-protein-coding RNAs have a wide variety of functions. A few examples are modifying chromosomes, regulating genes, influencing cell structure, and serving as precursors for small RNAs and microRNAs, which are involved in virus-host interactions.
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. That is why a transcriptome contains much more complex instructions than seems 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. Peng recalled, "There were intensive discussions about what value the new whole-transcriptome analysis would add to our understanding of viral pathogenesis. After several exploratory analyses, we realized that many long non-protein coding RNAs also responded to SARS virus infection. We were so excited. The response had just been overlooked by people."
"People have not seriously looked at these long-non-protein coding RNAs during viral infection," Peng noted, "because so little is known about these RNAs in general and this type of RNA can't be monitored easily with typical technologies." Katze and his research team were able to use highly advanced technologies, namely next generation sequencing, to perform a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection. The study was conducted in four strains of mice, some more susceptible to this virus or to the flu virus than others.
Through a comprehensive computational analysis of the data, the researchers observed that virus infection triggered about 500 long non-protein coding RNAs transcribed from known locations on the genome and about 1,000 from previously unspecified genomic regions.
"Using this approach," Katze noted, "we demonstrated that virus infection alters the expression of numerous long non-protein coding RNAs. These findings suggest that these RNAs may be a new class of regulatory molecules that play a role in determining the outcome of infection." The long non-protein coding RNAs may be helping to manage the infected animal's response to the virus, including the basic, first-line defense against infection -- the animal's innate, or inborn, immunity.
Another important finding was that the strains of more susceptible mice had a common profile showing distinct rates of genetic activity. This profile contained unique "signatures" of non-protein coding RNA activity. These signatures were associated with lethal infection. Test-tube studies show that more that 40 percent of the long non-coding RNAs and genomic regions activated in a SARS infection were also activated in response to both influenza virus infection and interferon treatment.
This finding further pointed to a signature profile associated with pathogenicity -- the power of a virus-host interaction to cause disease.
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Unique Signatures of Long Noncoding RNA Expression in Response to Virus Infection and Altered Innate Immune Signaling
Xinxia Peng a, Lisa Gralinski b, Christopher D. Armour c*, Martin T. Ferris d, Matthew J. Thomas a, Sean Proll a, Birgit G. Bradel-Tretheway a, Marcus J. Korth a, John C. Castle c*, Matthew C. Biery c*, Heather K. Bouzek c*, David R. Haynor c*, Matthew B. Frieman e, Mark Heise d, Christopher K. Raymond c*,
Ralph S. Baric b,f, and Michael G. Katze a
+Author Affiliations
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USAa;
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USAb;
Department of Molecular Informatics, Rosetta Inpharmatics LLC, Seattle, Washington, USAc;
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USAd;
Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USAe; and
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USAf
Address correspondence to Michael G. Katze, honey@u.washington.edu.
↵* Present address: Christopher D. Armour, Matthew C. Biery, and Christopher K. Raymond, NuGEN Technologies, Inc., Research and Development, San Carlos, California, USA; John C. Castle, Institute for Translational Oncology and Immunology, Mainz, Germany; Heather K. Bouzek, Department of Microbiology, University of Washington, Seattle, Washington, USA; David R. Haynor, Department of Radiology, University of Washington, Seattle, Washington, USA.
Editor Terence Dermody, Vanderbilt University Medical Center
ABSTRACT
Studies of the host response to virus infection typically focus on protein-coding genes. However, non-protein-coding RNAs (ncRNAs) are transcribed in mammalian cells, and the roles of many of these ncRNAs remain enigmas. Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross. We observed differential expression of approximately 500 annotated, long ncRNAs and 1,000 nonannotated genomic regions during infection. Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulatedin vitro in response to both influenza virus infection and interferon treatment. 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. At the same time, virus infection models provide a unique platform for studying the biology and regulation of ncRNAs.
IMPORTANCE Most studies examining the host transcriptional response to infection focus only on protein-coding genes. However, there is growing evidence that thousands of non-protein-coding RNAs (ncRNAs) are transcribed from mammalian genomes. While most attention to the involvement of ncRNAs in virus-host interactions has been on small ncRNAs such as microRNAs, it is becoming apparent that many long ncRNAs (>200 nucleotides [nt]) are also biologically important. These long ncRNAs have been found to have widespread functionality, including chromatin modification and transcriptional regulation and serving as the precursors of small RNAs. With the advent of next-generation sequencing technologies, whole-transcriptome analysis of the host response, including long ncRNAs, is now possible. Using this approach, we demonstrated that virus infection alters the expression of numerous long ncRNAs, suggesting that these RNAs may be a new class of regulatory molecules that play a role in determining the outcome of infection.
FOOTNOTES
M.J.T. performed qPCR experiments. X.P., S.P., M.J.T., and C.D.A. analyzed the data. X.P., C.D.A., S.P., J.C.C., M.H., C.K.R., R.S.B., and M.G.K. contributed to the concept, strategy, study design, and project management. X.P., L.G., C.D.A., M.F., B.G.B.-T., M.J.T., M.J.K., R.S.B., and M.G.K. wrote the manuscript.
Citation Peng, X., L. Gralinski, C. D. Armour, M. T. Ferris, M. J. Thomas, et al. 2010. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. mBio 1(5):e00206-10. doi:10.1128/mBio.00206-10.
Received 11 August 2010
Accepted 29 September 2010
Published 26 October 2010
Copyright © 2010 Peng et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
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