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Ebola Virus Appears to Undergo Distinct Changes in Bat, Human Host Cell Line Experiments

NEW YORK – New research from a University of California at San Francisco and University of Texas Medical Branch team suggests that the changes that arise in the Ebola virus (EBOV) as it grows in passaged cell lines differ depending on the host source of those cells, offering potential support for the notion that bats act as a natural reservoir for the often-deadly filovirus.

For a paper published in Cell Reports on Tuesday, the researchers used an existing circular sequencing (CirSeq) protocol to track changes in the RNA-based EBOV in human or bat cell lines during serial cell line passaging experiments. They noted that EBOVs grown in an EpoNi/22.1 renal cell line representing Epomops buettikoferi bats showed signs of RNA editing centered on glycan cap and mucin-like domain regions of the glycoprotein gene, for example, potentially reflecting a jump in activity by the bat host enzyme ADAR.

"This pattern fits expectations for a virus that uses bats as a natural reservoir, as evolution in the reservoir host would be drift-driven, while evolution in an incidental host would be more likely to favor positive selection for adaptation," the authors concluded.

The team picked up more pronounced apparent adaptive mutation patterns in EBOVs that had been sequentially grown in a 293T human embryonic kidney cell line, underscoring the distinct changes that may arise in EBOV depending on the infected host species that may, in turn, influence replication and other functional features in the virus.

An Ebola-related filovirus in the Marburgvirus genus has previously been linked to an Egyptian fruit bat reservoir species, the authors explained. While a definitive reservoir for EBOV is yet to be confirmed, the virus has been found in a handful of other bat species, including an Epomops species called E. franqueti that is closely related to the E. buettikoferi bat species behind the cell line used in the new study.

For their current look at Ebola adaptations within different host cells, the researchers relied in part on the error-prone and proofreading-poor nature of EBOV and other RNA-based viruses, using ultra-deep Illumina CirSeq experiments to uncover authentic mutations arising after a few rounds of passaging in the bat or human cells, while weeding out false-positive changes stemming from sequencing errors with computational methods.

"Clear differences in variant frequencies at the final passage highlight the distinct evolutionary paths of the 293T-passaged and EpoNi/22.1-passaged populations," they reported, noting that mutations tended to cluster in the EBOV glycoprotein regions after passaging in a manner that made them suspect enhanced activity by RNA editing enzymes in the ADAR family in the bat host.

The team went on to explore the potential fitness consequences of the mutations that turned up in each cell line with a combination of reverse genetics experiments to test infectious forms of the virus and a mini-genome system developed to study EBOV. 

"Our results offer insight into the effects of host factors on the evolution of EBOV and highlight the capacity of the virus to rapidly develop potentially adaptive mutations in diverse hosts," the authors reported. Given the current SARS-CoV-2 pandemic, and the likely origin of this virus in bats, "expanding our understanding of the evolution of viruses in their bat hosts is of particular relevance at this time," they concluded.