When a virus enters a host cell, it uses the cell’s transcription and translation machinery to produce the proteins necessary to create more viruses. A new paper describes a previously unknown mechanism that can occur during this process wherein the virus steals genetic signals from their hosts to expand their own genomes.

This finding is presented in a study titled, “Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection,” published in Cell.

The cross-disciplinary collaborative study was led by researchers at the Icahn School of Medicine at Mount Sinai in New York, and at the MRC-University of Glasgow Centre for Virus Research in the U.K.

The team of virologists worked with segmented negative-strand RNA viruses, which include viruses such as the influenza viruses and Lassa virus (the cause of Lassa fever).

Graphical abstract for Sook Yuin Ho et al.

The life cycles of these RNA viruses, the authors wrote, “depends on host mRNA, because viral polymerases cleave 5′-m7G-capped host transcripts to prime viral mRNA synthesis (“cap-snatching”).” The researchers hypothesized that start codons within cap-snatched host transcripts “could generate chimeric human-viral mRNAs with coding potential.”

Their findings suggest that viruses can produce previously undetected proteins by stealing genetic signals from their hosts. The researchers labeled them as UFO (Upstream Frankenstein Open reading frame) proteins, as they are encoded by stitching together the host and viral sequences. These UFO proteins can alter the course of viral infection and could be exploited for vaccine purposes. There was no knowledge of the existence of these kinds of proteins prior to this study.

“The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins,” said Ivan Marazzi, PhD, associate professor of microbiology at Icahn School of Medicine and corresponding author on the study. “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 ribosomes of the host’s cells. Viruses use the process of “cap-snatching,” in which they cut the end from one of the cell’s own mRNAs to make their own mRNA look like a message the host cell would normally translate.

“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,” said Marazzi.

The researchers report the existence of a mechanism of gene origination, which they named “start-snatching.” Depending on the reading frame, they wrote, “start-snatching allows the translation of host and viral ‘untranslated regions’ (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting.”

This makes it possible to translate previously unsuspected proteins from the hybrid host-virus sequences. They further showed 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, generate T cell responses, and contribute to 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.

Ed Hutchinson, PhD, corresponding author and a research fellow at MRC-University of Glasgow Centre for Virus Research, 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.”

Researchers say the next step in their work is to understand the distinct roles the unsuspected genes play. “Now we know they exist, we can study them and use the knowledge to help disease eradication,” said Marazzi. “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.”

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