Ever since the SARS outbreak of 2002, scientists have been trying to trace the history of the SARS-causing virus. Now virologist Ralph Baric has built a bat virus that simulates what the strain probably looked like just before it made the leap to infect humans.

Baric has been studying coronaviruses for twenty-five years. In 2003, when scientists identified a coronavirus, SARS-CoV, as the cause of severe acute respiratory syndrome (SARS), his lab built the first working molecular clone of the virus. (See Endeavors, Fall 2003, “Stalking SARS.”)

It’s been five years since the last recorded case of SARS, but that hasn’t stopped Baric from continuing to study the virus and its relatives. He knows that SARS-CoV, or something very like it, could — and probably will — come back. “Precedent suggests that it’s inevitable,” he says. Ebola went silent for about ten years between outbreaks. Chikungunya, a mosquito-borne virus native to Asia, disappeared for twenty years before reemerging in the late 1990s.

Ebola and chikungunya can tell us something about SARS-CoV because all three are zoonotic viruses, meaning that they can jump from nonhuman animals to humans or vice versa. So even when they’re not infecting humans, the viruses — or their close relatives — are still getting passed around in animal populations.

SARS-like viruses have infected several species, including horseshoe bats, civet cats, and humans — in that order, according to a widely accepted model. Baric agrees that the virus moved between civet cats and humans, but he thinks it might first have jumped from bats straight to humans. “When you compare their DNA sequences, the bat strains appear to be closer to the human side than the cat side,” he says.

Baric and his collaborators think that SARS-CoV came about when bat coronaviruses recombined with each other, forming a new strain that infected humans. If this is true, then SARS-CoV might still be hanging out in bats, and human reinfection could occur at any time. Whether or not that hypothesis is correct, bats are still a reservoir of SARS-like coronaviruses that could mutate to jump species again. That’s why Baric’s been studying everything he can about the bat virus strains.

His team used genome sequence data from a National Institutes of Health database to make the synthetic bat virus. There’s a small region of the virus called the receptor binding domain (RBD) — the part that determines what kind of host the virus can latch on to. The team gave the synthetic virus the right genes to allow its RBDs to bind to human cells. “This simulates the recombination that might have occurred in a mixed infection,” Baric says.

As soon as he had the bat virus with the SARS-like RBD, Baric started experimenting with it in mice, which are susceptible to the same RBD as humans. Baric will soon publish data on a vaccine platform that prevents some SARS-like viruses from infecting mice, including elderly mice, who, like elderly humans, are the population most likely to die of SARS.

That’s not enough for Baric, who is studying more bat coronaviruses to try to improve the vaccine’s range. His team wants to build a vaccine platform that offers the flexibility of modern flu vaccines, which are genetically altered each year to fight current virus strains. “We want to be able to respond quickly next time any of these viruses reemerge,” he says.

The bat coronavirus reconstruction project, presented in December 2008 in the Proceedings of the National Academy of Sciences, was colead by Mark Denison, a professor of pediatrics at Vanderbilt University. Baric received funding from the National Institute of Allergy and Infectious Diseases and the Gillings Innovation Fund.