Many mBiosphere readers will have seen Contagion, the 2011 movie about a worldwide viral pandemic. In the movie, a deadly new virus spreads throughout the world, leaving those infected dead and those uninfected to deal with vast societal upheaval (as dangerous a consequence as disease itself). The movie is a fascinating look at the impact of emerging diseases on our relationships, society, and interactions, and the ending clip implies the origin of that pandemic:
That’s right: bats. Many emerging viruses (such as SARS-CoV, Ebola virus, and the Henipavirus genus) are thought to have zoonotic reservoirs in the regional bat populations. Bats offer a threat to spreading these viruses because their flight capacity makes them readily mobile. Also, there are a whole lot of them: with 925 different (known) species, bats make up 20% of total mammals on Earth. Their large numbers increase the likelihood that a virus infecting these flying mammals might be passed to another species, rather than remaining isolated in the bat population.
Often, these viruses are found after having jumped into humans and causing an outbreak of disease. These discoveries involved intensive fieldwork and are hugely labor-intenstive. Last week, however, researchers discovered a new virus in an established cell line of bat cells, giving researchers the fortunate experience to characterize a new bat virus.
The research, conducted by first author Reed Shabman and lead scientist Christopher Basler and published in mSphere, was initially conducted to characterize the bat cell line response to viral infection. This is an important question, because the ability to understand (and maybe someday manipulate) the bat immune response to infection may help stave off virus crossover, preventing future zoonotic outbreaks. But when the scientists performed deep sequencing on the bat cell mRNAs, they found sequences with homology to known herpesvirus mRNAs, leading to the discovery of a novel gammaherpesvirus.
Although discovered in bats, the scientists wanted to test whether cell lines from other mammals would support viral replication. They inoculated the newly discovered virus, dubbed bat gammaherpesvirus 8 (BGHV8), into Vero cells, which is a cell line derived from African green monkey kidney. Not only did these cells support viral replication, but so did cell lines derived from both human lung and liver (A549 and Huh7 cell lines, respectively). Vero cells were found to undergo a lytic replication, and monolayers of Vero cells were destroyed by BGHV8 infection.
While the BGHV8 genome was found to have similar organization as related gammaherpesviruses, the accessory ORFs were some of the most informative sequences, Herpesvirus accessory ORFs (those not directly related to viral replication, assembly, or structure) are often viral homologues to genes from the vertebrate host that they infect. For example, Kaposi’s sarcoma-associated herpesvirus (KSHV), which causes Kaposi’s sarcoma, was recently found to contain an ORF that generates a viral copy of a human immune protein called IL-6. Expression of IL-6 from KSHV-infected cells allows manipulation of the human immune system. This ORF-host association spurred Shabman and Basler to investigate the BGHV8 accessory ORFs.
The accessory ORFs, shown in blue in the figure at left, closely resembled sequences from bats, suggesting that the bat cell line from which the virus was isolated naturally harbored the virus, probably even before the bat cells were immortalized. In fact, the known role of gammaherpesviruses as oncoviruses suggests the BGHV8 may even have contributed to the cell line immortalization. This helps eliminate contamination from nearby cell lines (or nearby grad students) as the original viral source. While proof that the virus is found in wild bats requires isolating the virus from a wild-caught animal, the evidence that the virus is a natural bat infection is strong.
Other bat gammaherpesviruses have been found, but only in sequence results – this is the first study to identify the replication-competent virus itself. “This is the first replicating bat gammaherpesvirus that’s been isolated,” says first author Shabman. “Most labs just have bits and pieces of a virus.” Passage of bat cell supernatant was sufficient to infect Vero cells, suggesting that the virus in the bat cells continues to produce infectious virus. The ability of this BGHV8 to infect human cell lines has the authors urging caution in studying the virus, with BSL-2 level safety precautions advised to prevent potential researcher contamination.
Now that the virus has been identified, Basler and his group plan to use it to address several important questions. Understanding a virus that naturally infects bats will allow scientists to focus on why bats act as frequent reservoirs for emerging viruses. “We have very few tools to study bats’ immune response to viruses,” says Basler. “This natural bat virus is actually going to prove to be useful in understanding and probing how bats respond to natural infections and microorganisms that can cause disease.”
-- Julie Wolf