Approximately 18 million years ago, genes encoding viral proteins 35 (VP35s) integrated into the genomes of Myotis (mouse-eared) bats. Produced by the highly deadly Ebola and Marburg viruses, VP35s suppress the host immune system and play a critical role in the efficient replication and virulence of these filoviruses. A study publishing July 24 in Cell Reports sheds light on the potential functional role of these so-called non-retroviral integrated RNA viral sequences (NIRVs) in bats. Despite their structural similarity, Myotis VP35s are less potent immune suppressors than filoviral VP35s, and that difference could potentially reduce the susceptibility of bats to viral infection.
"We are the first to study in detail a family of NIRVs from a combined evolutionary, structural, and functional perspective," says senior author Christopher Basler of Georgia State University. "The study also provides a unique and interesting perspective on how Ebola virus and related viruses can interact with the host. We think of Ebola virus as a deadly virus, but in the past, Ebola virus essentially donated one of its genes to the benefit of Myotis bats."
NIRVs are rare mutations thought to result from the integration of viral genes from RNA viruses into a host species genome through the co-option of a host reverse transcriptase--an enzyme that catalyzes the formation of DNA from an RNA template. NIRVs are common in eukaryotic genomes and are present in fungi, plants, insects, and mammals. For example, VP35 sequences have been identified in seven genera of mammals and include the tammar wallaby, the Philippine tarsier, rodents, and all members of the Myotis genus.
"NIRVs serve as a viral fossil record, providing evidence of historical viral interactions with a host and allowing for the study of the timescale and evolution of the virus-host interaction," says first author Megan Edwards of Georgia State University. "But relatively little is known about the biological significance of these genetic elements."
To address this question, Basler and Edwards teamed up with Daisy Leung of Washington University School of Medicine and Derek Taylor of the University at Buffalo to characterize VP35s from 16 different species of Myotis bats, as well as VP35s from Ebola and Marburg viruses. Surprisingly, the structure of bat VP35 remains, after millions of years, nearly identical to its viral counterparts. But compared with filoviral VP35s, the Myotis VP35s were less potent suppressors of the production of an antiviral immune protein called interferon beta (IFNβ) in human and Myotis cells. According to the authors, it is likely that a potent suppressor of interferon responses would be selected against because it could result in high susceptibility to viral infection.
"Our study provides the most detailed characterization available of the effect of multi-million-year evolution on the structure and function of a NIRV, identifying striking structural conservation and related but altered function to the viral VP35 gene," Edwards says. "The Myotis VP35 could have a regulatory role in the Myotis immune response, where you would expect the host to keep its immune system intact. The VP35-like gene in Myotis bats could also have other roles that we are not yet aware of."
To gain further insight into the functional significance of Myotis VP35s, the researchers will examine tissue-specific and developmentally regulated expression patterns. "We don't know with certainty what the VP35 genes do for the bat," Basler says. "We will continue to study how the VP35 gene may benefit Myotis bats, because this provides new insight into the relationship between bats and these viruses."
This work was supported by NIH, the Department of the Defense, and the Defense Threat Reduction Agency.
Cell Reports, Edwards et al.: "Conservation of structure and immune antagonist functions of filoviral VP35 homologues present in microbat genomes" https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30955-0
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