Scientists have shown that a large group of viruses, including the influenza viruses and other serious pathogens, steal genetic signals from their hosts to expand their own genomes.
The study – a collaboration between the University of Glasgow and researchers at the Icahn School of Medicine at Mount Sinai in New York, and published recently in Cell – shows that, by stealing genetic signals from their hosts, viruses can produce a wealth of previously undetected proteins.
There was no knowledge of the existence of these new proteins, called UFOs – Upstream Frankenstein Open reading frame proteins – prior to this study.
The scientists showed that the UFO proteins – so called because they are encoded by stitching together the host and viral sequences – can alter the course of viral infection and could be exploited for vaccine purposes.
To do the study, the cross-disciplinary team of virologists – from the MRC-UofG Centre for Virus Research (CVR) and the Global Health and Emerging Pathogens Institute – looked at a large group of viruses known as segmented negative-strand RNA viruses (sNSVs). These include widespread and serious pathogens of humans, domesticated animals and plants, including the influenza viruses and Lassa virus (the cause of Lassa fever).
Ed Hutchinson, PhD, corresponding author and a research fellow at the CVR, said, “Viruses take over their host at the molecular level, and this work identifies a new way in which some viruses can wring every last bit of potential out of the molecular machinery they are exploiting.
“While the work done here focusses on influenza viruses, it implies that a huge number of viral species can make previously unsuspected genes.”
Ivan Marazzi, PhD, Associate Professor of Microbiology at Icahn School of Medicine and co-corresponding author on the study, said: “The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins.
“To understand how a pathogen antagonizes the host and establishes infection, we need to have a clear understanding of what proteins a pathogen encodes, how they function, and the manner in which they contribute to virulence.”
Viruses cannot build their own proteins, so they need to feed suitable instructions to the machinery that builds proteins in their host’s cells. Viruses do this through a process called “cap-snatching,” in which they cut the end from one of the cell’s own protein-encoding messages (a messenger RNA, or mRNA) and then extend that sequence with a copy of one of their own genes. This gives a hybrid message to be read.
Dr. Marazzi added: “For decades we thought that by the time the body encounters the signal to start translating that message into protein (a ‘start codon’) it is reading a message provided to it solely by the virus. Our work shows that the host sequence is not silent.”
The researchers show that, because they make hybrids of host mRNAs with their own genes, viruses (sNSVs) can produce messages with extra, host-derived start codons, a process they called “start snatching.” This makes it possible to translate previously unsuspected proteins from the hybrid host-virus sequences.
They further show that these novel genes are expressed by influenza viruses and potentially a vast number of other viruses. The product of these hybrid genes can be visible to the immune system, and they can modulate virulence.
Further studies are needed to understand this new class of proteins and what the implications are of their pervasive expression by many of the RNA viruses that cause epidemics and pandemics.
Researchers say the next part of their work is to understand the distinct roles the unsuspected genes play.
Dr. Marazzi added: “Now we know they exist, we can study them and use the knowledge to help disease eradication. A large global effort is required to stop viral epidemics and pandemics, and these new insights may lead to identifying novel ways to stop infection.”
Reference: “Hybrid Gene Origination Creates Human-VirusChimeric Proteins during Infection” by Jessica Sook Yuin Ho, Matthew Angel, Yixuan Ma, Elizabeth Sloan, Guojun Wang, Carles Martinez-Romero, Marta Alenquer, Vladimir Roudko, Liliane Chung, Simin Zheng, Max Chang, Yesai Fstkchyan, Sara Clohisey, Adam M. Dinan, James Gibbs, Robert Gifford, Rong Shen, Quan Gu, Nerea Irigoyen, Laura Campisi, Cheng Huang, Nan Zhao, Joshua D. Jones, Ingeborg van Knippenberg, Zeyu Zhu, Natasha Moshkina, Léa Meyer, Justine Noel, Zuleyma Peralta, Veronica Rezelj, Robyn Kaake, Brad Rosenberg, Bo Wang, Jiajie Wei, Slobodan Paessler, Helen M. Wise, Jeffrey Johnson, Alessandro Vannini, Maria João Amorim, J. Kenneth Baillie, Emily R. Miraldi, Christopher Benner, Ian Brierley, Paul Digard, Marta Łuksza, Andrew E. Firth, Nevan Krogan, Benjamin D. Greenbaum, Megan K. MacLeod, Harm van Bakel, Adolfo Garcìa-Sastre, Jonathan W. Yewdell, Edward Hutchinson and Ivan Marazzi, 18 June 2020, Cell.
This study was supported by funders including the National Institute of Allergy and Infectious Diseases and the UK Medical Research Council.
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