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With Synthetic Biology Approach, Researchers Characterize Bat Influenza Virus

NEW YORK (GenomeWeb) – Using a synthetic biology-based approach, researchers from the J. Craig Venter Institute and Kansas State University found that a bat influenza virus uncovered in 2009 poses little-to-no pandemic threat to humans.

Though the researchers found that this bat flu virus, called H17N10, was viable, they couldn't directly study it. They could, however, culture a modified version of the virus in which the original hemagglutinin and neuraminidase coding regions were swapped with those from a lab-based H1N1 strain. This modified virus could replicate in vitro as well as in mice, as the researchers reported in PLOS Pathogens today.

"The nice thing about the synthetic biology approach is that you can keep going back to the well," David Wentworth, who is now at the US Centers for Disease Control and Prevention, told GenomeWeb Daily News. "You have that DNA, you can make more of it, whereas if you have a piece of a tissue and you do something to it, you've lost [it]."

Bats are a reservoir of a number of zoonotic viruses, such as SARS, that can infect humans, Wentworth said. But whether this bat influenza virus, uncovered in Guatemalan little yellow-shouldered bats by a separate group as bits of viral sequence, could infect people was unclear, as it couldn't be cultured.

Wentworth and his colleagues synthesized the complete genome of that Guatemalan bat influenza virus, based on the previous group's published sequence. They cloned the virus, dubbed Bat09, into reverse genetics plasmids to produce influenza-like RNA particles. Those influenza-like RNA then underwent replication using transfected proteins the researchers also supplied. A viable virus, then, produces a particle. The Bat09 virus, Wentworth noted, produced such particles.

However, when they transferred those Bat09 particles into chicken eggs and cell lines derived from a number of animals, including swine, humans, and free-tailed bats, the particles didn't cause an infection.

As previous studies of the Bat09 virus indicated that its surface hemagglutinin and neuraminidase proteins are likely adapted to bats and don't act as other flu HA or NA proteins do, the researchers swapped the Bat09 HA and NA coding regions for ones from the lab-adapted H1N1 virus PR8, keeping some of the Bat09 sequences at the termini.

This engineered Bat09 virus could replicate in and infect mice with virulence similar to that of the PR8 lab virus. The virus could also be rescued when attached to HA and NA protein coding regions from an H3N2 virus.

While Wentworth and his colleagues noted that some of the observed pathogenicity of the modified Bat09 virus is likely due to the PR8 HA and NA proteins, they added that the bat influenza internal proteins — the unmodified parts of the engineered virus — support replication of the virus in vitro, in eggs, and in mouse lungs.

The modified Bat09 virus, the researchers noted, appeared to be fairly stable in mice, though sporadic SNPs did arise as the virus was passaged through cells. This, they said, indicates that bat influenza viruses are mammalian viruses, though they've been in bats for a long while.

Still, the bat influenza viruses appear to be distinct from influenza A or influenza B viruses.

The researchers noted that the some of the internal Bat09 protein-coding genes have striking features. For instance, position 627 of its PB2 protein is a serine residue, unlike either mammalian or avian influenza A virus. Switching that residue to the mammalian lysine residue in the modified bat virus led to increased viral replication, though it remained attenuated in the mouse.

Additionally, the bat influenza viruses cannot easily reassort with influenza A viruses, the researchers reported. Reassortment enables the virus to shuffle up its eight-segmented genome with other flu viruses that may be infecting the same cell, leading to a greater variety of viruses, and how efficiently two viruses can reassort typically reflects how divergent the viruses are.

"What we show here is that the bat virus that we were able to generate, doesn't reassort with influenza A viruses in any sort of efficient manner," Wentworth said.

Another bat influenza, identified in 2010 in Peru, was fully compatible with Bat09 and could efficiently resassort, the researchers said. In their paper, they suggested that these two bat influenza virus lineages be classified as a new genus or species within Orthomyxoviridae.

Because this bat virus couldn't be grown in any human cells in the lab and because it can't reassort efficiently, Wentworth said it poses a low risk to humans. He added, though, that there is still a small risk and that other bat flu viruses may be different.

"While there might be some risk, it's not great. We don't see how [this bat influenza and a human influenza virus] would reassort even if they got in the same host cell," Wentworth said. "And it looks unlikely that they'd get into the same host cell."