A ‘Kill Switch’ For H7N9 and H5N1 ‘Gain-Of Function’ Influenza Viruses

11 August 2013 by Nsikan Akpan, posted in Applications, TBS Journal Club

 A report in Nature Biotechnology highlights a simple way to control gain-of-function flu viruses.

Influenza A (H7N9) as viewed through an electron microscope. Both filaments and spheres are observed in this photo. (Credit: The U.S. Centers for Disease Control and Prevention | wikimedia)

Days after the controversial announcement that scientists want to conduct “gain-of-function” H7N9 influenza research, which may create more potent strains of the virus, researchers from Mount Sinai offer a clever solution that could keep these lab-enhanced “Frankenstein” germs from causing disease in human cells.

GOF, The Sequel

Two years ago, Ron Fouchier – a virologist at Erasmus MC – shocked the scientific community by announcing his lab had genetically altered H5N1 avian influenza so it could easily spread between ferrets via the air. Ferrets are used to model flu transmission in humans, so concerns were raised over what might happen if this new strain accidentally escaped the lab.

H5N1 is a potent killer, causing fatality in ~50 percent of cases, but natural variants don’t readily jump from person-to-person, which experts regard as the main reason for why the virus has never caused a widespread outbreak.

Fouchier’s findings, along with similar work by Yoshihiro Kawaoka at the University of Wisconsin, sparked an intense debate, by academics and in the international media, over the safety of gain-of-function flu research.

News story after news story brought up the same questions:

Could the viruses cause a human pandemic if they were released from the lab?

Were the right safety protocols to keep this from happening?

Had scientists exceeded their mandate and put the whole world at risk?

These concerns1 snowballed and ultimately halted this line of research until earlier this year.

Now Fouchier, Kawaoka, and 20 other scientists want to create a sequel by conducting gain-of-function research on the H7N9 influenza, which emerged in China earlier this year. The group, who points out that H7N9 and H5N1 could evolve into more dangerous forms on their own in the wild, contend that these experiments will advance our understanding of influenza and prepare us for a possible cataclysmic event.

A ‘Kill Switch’ Engineered Flu Viruses

Since genetic tinkering with virus got us into this potential mess, maybe it could find a way out? At least that’s the rationale behind a new study from Mount Sinai School of Medicine that may ease everyone’s fears over gain-of-function research.

The key to this safeguard: microRNA. MicroRNA are tiny strands of genetic material that can serve as on-and-off switch for genes.

Different species express different microRNA molecules, so the team tailored lab-borne flu viruses so that their genes would be turned off by a microRNA found in human cells, but not in the animal models being used by scientists.

The researchers isolated one microRNA molecue – miR-192 – that is abundantly found in lung cells from humans and mice, but not in ferrets2.

Next to test the concept, they tweaked an H3N2 influenza virus – a major source of seasonal flu case – so the production of its gene for hemagglutinin would be blocked by miR-192. Hemagglutinin is necessary for viral entry and infection.

The researchers found that the modified H3N2 virus was still swapped by ferrets living in close quarters, but failed to cause disease in mice and could no longer infect human cells grown in a dish.

“These data demonstrate that species-specific miRNAs can be exploited to mitigate the potential risks associated with transmis­sion studies of influenza A virus,” write the authors who were led by Drs. Daniel Perez, Adolfo García-Sastre, and Benjamin tenOever, who called this approach “molecular biocontainment”.

Dubbing this approach “molecular biocontainment”, the researchers note that:

"this strategy is not necessarily restricted to influenza A virus. It may also be used to minimize risks associated with potential gain-of-function experiments of other highly pathogenic viruses including Ebola, SARS coronavirus and henipa­viruses, among others. The only requirements for this approach are miRNAs that are absent in cells of the model system where replication is meant to occur but present in human cells, and a genetic system to permit the insertion of miRNA target sites into the genome.”

 

Source: Langlois RA, Albrecht RA, Kimble B et al. MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies. Nature Biotechnology.2013.

 

Geek Notes:

1. Crossing Back Over The Rubicon

It’s funny that so much fear was created over these manufactured viruses, given the five mutations that allowed for airborne transmission in ferrets, also made the germs less lethal...or as Columbia University virologist Vincent Racaniello astutely observed earlier this week: “Gain-of-function is almost always accompanied by a loss-of-function.

 

2. The team had another criteria for their miRNA search in they looked for one that isn’t present in MDCK cells, a canine kidney cell line that is frequently used for influenza studies.

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