Scientists Identify Antivirus System in Host Cells
ScienceDaily (Nov. 18, 2010) — Viruses have led scientists at Washington University School of Medicine in St. Louis to the discovery of a security system in host cells. Viruses that cause disease in animals beat the security system millennia ago. But now that researchers are aware of it, they can explore the possibility of bringing the system back into play in the fight against diseases such as sudden acute respiratory syndrome (SARS), West Nile virus, dengue and yellow fever.
West Nile virus (brown) infects neurons, whose nuclei are the round purple-blue spots. Scientists have discovered a new anti-virus system in host cells by studying how viruses like West Nile defeated the system. It may one day be possible to use pharmaceuticals to bring this security system back online in the fight against diseases such as West Nile, sudden acute respiratory syndrome (SARS), dengue and yellow fever. (Credit: Michael Diamond, MD, PhD)
The findings, published in Nature,solve a 35-year-old mystery that began when National Institutes of Health researcher Bernard Moss, MD, PhD, noticed that poxviruses put chemical "caps" on particular spots in every piece of genetic material transcribed from their DNA. That transcribed material is RNA; to reproduce, viruses need to trick the host cell into making viral proteins from this RNA.
Noting evidence that the host cell puts caps on its own RNA in identical positions, Moss theorized that the caps might be a way for cells to distinguish between their RNA and that of an invader. He guessed the caps might serve as a sort of fake identification badge for the virus' RNA, allowing it to bypass host cell security systems primed to attack any RNA lacking the caps.
Since Moss's study, scientists have learned that some viruses have strategies for stealing RNA caps from host cells and putting them on their own RNA. Several disease-causing viruses have to make their own caps, including:
poxviruses, which cause smallpox
flaviviruses, which cause West Nile encephalitis, yellow fever and dengue;
rhabdoviruses, which cause rabies;
coronaviruses, which cause SARS;
reoviruses, which cause mild respiratory distress or diarrhea.
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Letter
Nature 468, 452-456 (18 November 2010) | doi:10.1038/nature09489; Received 24 February 2010; Accepted 13 September 2010; Published online 17 November 2010
2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members
Stephane Daffis1,14, Kristy J. Szretter1,14, Jill Schriewer5, Jianqing Li2, Soonjeon Youn1, John Errett6, Tsai-Yu Lin7, Stewart Schneller8, Roland Zust9, Hongping Dong11, Volker Thiel9,10, Ganes C. Sen12, Volker Fensterl12, William B. Klimstra13, Theodore C. Pierson7, R. Mark Buller4,5, Michael Gale Jr4,6, Pei-Yong Shi4,11 & Michael S. Diamond1,2,3,4
Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
Department of Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
Midwest, Pacific Northwest, and Northeast Regional Centers for Biodefense and Emerging Infectious Diseases Research
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA
Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA
Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849-5312, USA
Institute of Immunobiology, Kantonal Hospital St Gallen, 9007 St Gallen, Switzerland
Vetsuisse Faculty, University of Zürich, 8006 Zürich, Switzerland
Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA
Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
Department of Microbiology and Molecular Genetics, University of Pittsburgh Medical School, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, USA
These authors contributed equally to this work.
Correspondence to: Michael S. Diamond1,2,3,4
Email: diamond@borcim.wustl.edu
Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′-Opositions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability1, the function of 2′-O methylation has remained uncertain since its discovery 35 years ago2, 3, 4. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2′-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2′-Omethylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2′-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2′-O methylation of the 5′ cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2′-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.
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