June 19, 2020 -- Certain types of RNA viruses may be capable of using host RNA to expand their own genetic repertoire, according to a new study published in Cell on June 18. This mechanism may enable viruses to overcome the limitations of small genomes and more effectively infect host cells.
Segmented negative-strand RNA viruses contain some serious pathogens such as influenza A and Lassa viruses. The genetic material of these viruses is complementary to mRNA and must be converted to positive RNA by RNA polymerase before translation.
These viruses make direct use of the 5' termini of host mRNA to transcribe their own genes, participating in a mechanism called "cap-snatching" whereby viral mRNA synthesis is primed using host RNA sequences capped with methyl-7-guanosine at the 5′ end, which the viral polymerase cleaves from host RNA polymerase II transcripts. This process results in genetic hybrids of host and viral sequences that enable the viruses to be transcribed by host machinery.
"The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins," said author Ivan Marazzi, PhD, associate professor of microbiology at Icahn School of Medicine, in a statement. "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."
In the current study, an interdisciplinary group of virologists from the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai and at the Medical Research Council (MRC)-University of Glasgow Centre for Virus Research in Scotland hypothesized that segmented negative-strand RNA viruses can obtain functional upstream start codons (uAUGs) by stealing the 5' terminal mRNA sequences from their hosts via a mechanism called "start-snatching." Resulting translation from host-derived upstream start codons in chimeric host-viral transcripts ultimately expands the viral proteome, specifically in open reading frames (ORFs).
"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," Marazzi said.
The researchers found that around 10% of influenza A viruses tested contained host-derived start codons. Furthermore, the upstream viral ORFs (uvORFs) were successfully translated in some of the influenza virus samples.
The team identified at least two novel hybrid peptides derived from uvORFs in transcription primer locations, which they named PB1-UFO and PB2-UFO (UFO standing for upstream Frankenstein ORF). UFOs were so termed because they are encoded by stitching together the host and viral sequences. Start-snatching can also result in canonical viral proteins with N-terminal extensions.
The translation products of the hybrid genes can be detected by the immune system and may even modulate virulence. Further studies are needed to understand this novel class of proteins and the implications of their pervasive expression by many of the RNA viruses that cause epidemics and pandemics.
Because these chimeric genes and uvORFs are expressed in segmented negative-strand RNAs such as influenza A viruses, the researchers explored who benefits from their expression. Based on the fact that full-length PB1-UFO were present in more than 75% of all influenza isolates and N-terminal extensions were present in more than 99% of isolates, researchers believe that multiple forces drive the virus to maintain the sequences and influence their eventual replication.
"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," said author Ed Hutchinson, PhD, research fellow at MRC-University of Glasgow Centre for Virus Research. "While the work done here focuses on influenza viruses, it implies that a huge number of viral species can make previously unsuspected genes."
The researchers noted that in the future they plan to understand the direct role that the hybrid genes play and to leverage that knowledge to help eradicate diseases.
"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," Marazzi said.
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