SARS - severe acute respiratory syndrome - alarmed the world five years ago as the first global pandemic of the 21st century.
The coronavirus (SARS-CoV) that sickened more than 8,000 people - and killed nearly 800 of them - may have originated in bats, but the actual animal source is not known.
In an effort to understand how SARS-CoV may have jumped from bats to humans, a team of investigators from Vanderbilt University Medical Center and the University of North Carolina at Chapel Hill has now generated a synthetic SARS-like bat coronavirus. The virus - the largest replicating synthetic organism ever made - is infectious in cultured cells and mice, the researchers report in the Proceedings of the National Academy of Sciences .
The findings identify pathways by which a bat coronavirus may have adapted to infect humans. The studies also provide a model approach for rapid identification, analysis and public health responses to future natural or intentional virus epidemics.
Zoonotic viruses - animal pathogens that can cause disease in humans - pose a serious threat to public health, said Mark Denison, M.D., professor of Pediatrics at Vanderbilt and a co-leader of the research with Ralph Baric, Ph.D., professor of Epidemiology at UNC.
"It's becoming more and more clear that new human epidemics will continue to originate in animals," said Denison, who is also an associate professor of Microbiology & Immunology. "However, the mechanisms of trans-species movement and adaptation of viruses from animals to humans remain poorly understood."
At the time of the SARS epidemic, the culprit virus was rapidly identified as a coronavirus (SARS-CoV). But it didn't look like the two human coronaviruses that were known, which cause 20 percent to 30 percent of common colds, and the animal "reservoir" (the original animal host for the virus) remained elusive.
Investigators became convinced that bats were the likely source, but bat coronaviruses had never been successfully grown in culture or animals, which blocked studies of replication, evolution and prevention.
The Denison and Baric teams, with lead authors Michelle Becker, Ph.D., of Vanderbilt, and Rachel Graham Ph.D., of UNC, determined that not being able to grow the virus represented a critical gap in the ability to rapidly identify and respond to new pathogens.
To address this vulnerability, the team decided to use synthetic biology to recover a non-cultivatable virus.
"The idea is, here's the virus, or the virus group, that we think became SARS-CoV," Denison said. "Let's see if we can synthetically recover the bat virus and test it in cultured cells and in animal models - let the bat virus show us the pathways that it may have used to become a human pathogen.
"Then we would have a viable candidate virus to test for diagnostics, vaccines and treatment."
The investigators used published SARS-like bat coronavirus sequences to establish a "consensus" genome sequence - "the best bet for a virus genome that would be viable," Denison said. They then used commercial DNA synthesis and reverse genetics to "build" the consensus viral genome and several variations.