Identifying a killer

When the first human retroviruses, including HIV, were discovered in the '70s and '80s, decades of research on animal retroviruses allowed researchers and clinicians to rapidly develop diagnostics, treatments, and preventive measures for the emerging human diseases.

History is repeating itself as the world public health community draws on decades of research on animal coronaviruses to help them understand and battle the emergent human coronavirus, severe acute respiratory syndrome.

On March 12, 2003, the World Health Organization issued a global alert for cases of atypical pneumonia in response to reports of an unidentified severe respiratory illness spreading in China and Vietnam. Within days, the WHO had assembled an international team of laboratories to identify the SARS pathogen.

Meanwhile, in the United States the national Centers for Disease Control and Prevention had begun contacting experts on coronaviruses, a family of RNA viruses known to cause severe respiratory and intestinal disease in many species of animals. They suspected SARS was a coronavirus. Within a month, several laboratories around the globe, including a CDC laboratory, had sequenced the genome of the SARS virus.

The journal Science, published by the American Association for the Advancement of Science, released the first peer-reviewed genomic studies of two strains of SARS on May 1. The studies are posted on Science Magazine's Web site, www.sciencemag.org/feature/data/sars/.

At press time in May, a cumulative total of 7,000 SARS cases with more than 500 deaths had been reported from 29 countries, according to the WHO.

Prior to the identification of SARS, only two coronaviruses were known to cause illness in humans, and those viruses cause only minor cold symptoms, according to Dr. Thomas G. Ksiazek, a veterinarian and the chief of the Special Pathogens Branch in the CDC Division of Viral and Rickettsial Diseases. There are several coronaviruses, however, that are known to cause severe respiratory and intestinal diseases in animals.

"Much of the knowledge about coronaviruses comes from research on economically important diseases (in food animals)," Dr. Ksiazek said.

Dr. David A. Brian, a veterinarian and coronavirus expert at the University of Tennessee who studies coronaviruses in humans, mice, swine, and bovids, provided reagents to the CDC that his laboratory uses to sequence coronavirus genomes.

SARS is unusual in a number of respects, Dr. Brian said. He explained that there are three groups of coronaviruses—two infect mammals, one infects birds. The genetic sequence of SARS is unique, but it shares similarities with coronaviruses in all three groups. Some experts have proposed creating a forth group for SARS, but no change has yet been made.

"It doesn't seem to come from any known coronavirus," said Jack Gelb, PhD, a professor and virologist at the University of Delaware.

Despite the uniqueness of the virus, experts warn against panicking in the face of the outbreak. SARS has a relatively low mortality rate, 4 percent to 15 percent, compared with some of the animal coronaviruses, which may have mortality rates of up to 100 percent.

While epidemiologic investigations are continuing, Dr. Ksiazek said the CDC's priority is identifying areas where the virus is spreading, alerting travelers accordingly, preventing transmission—particularly among medical workers, and developing diagnostic tests.

At press time, scientists had successfully infected primates with the SARS virus in experimental conditions, but zoonotic transmission of the disease under natural conditions has not been confirmed, according to the WHO.

"We don't know yet if SARS can be transmitted to domestic animals, or if domestic animals can harbor the coronavirus and pass it to humans," Dr. Brian said. "We don't know the full host range of the SARS virus."

Lessons learned
Physicians and epidemiologists working to understand, prevent, and treat SARS are drawing on the experience and knowledge of the veterinary and animal science community.

Dr. Niels C. Pedersen, director of the Center for Companion Animal Health and the Veterinary Genetics Laboratory at the University of California-Davis, was one of three veterinarians and animal scientists invited to join a CDC SARS advisory group. Linda Saif, PhD, a professor in the Food Animal Health Research Program at The Ohio State University, and Dr. Christopher Olsen an associate professor at the University of Wisconsin-Madison, were also invited to participate.

Dr. Pedersen said the advisory group discussed some of the characteristics of coronaviruses in animals that may be important to understanding SARS.

Among the issues discussed was the ability of coronaviruses from various species to swap genes. Some of the feline coronaviruses, for example, have incorporated genes from swine and canine coronaviruses, Dr. Pedersen said.

Dr. Jim Guy, an avian coronavirus at North Carolina State University, explained that coronaviruses may swap genes when they infect the same animal cell simultaneously.

"It probably happens all the time," he said.

Another characteristic of coronaviruses that might be important to the SARS investigation is the ability of bovine and swine coronaviruses to shift from causing disease in the digestive tract to causing disease in the respiratory tract, Dr. Pedersen said. Though SARS, so far, has caused only respiratory disease, there is some evidence that the virus is shed in feces, he said.

There are also similarities between the immune responses of humans infected with SARS and the immune responses of cats infected with feline infectious peritonitis, a feline coronavirus. In both species, when the disease is fatal there is evidence of a tremendous—but unsuccessful—immune response to a very small amount of virus.

"SARS patients—the ones that die—don't seem to be able to shake it off," Dr. Pedersen said.

The vaccines for animal coronaviruses are also an area of interest to SARS investigators. There has been much debate among the veterinary community about the efficacy of animal coronavirus vaccines.

Dr. Brian explained that the Department of Agriculture regulates veterinary vaccines and "requires only proof of safety, not proof of efficacy." Not enough studies have been done on the efficacy of the vaccines available, he said.

Another challenge clinicians face when vaccinating against coronaviruses is that vaccines are strain specific and if there are multiple strains of the virus, animals at risk should be vaccinated against all strains.

"Avian infectious bronchitis has been controlled fairly well by vaccination, but its strain specific in that there are multiple sterotypes you have to protect against," Dr. Guy said.

Dr. Ksiazek said information about existing animal vaccines might aid the development of a human vaccine.

"They do provide a model on which to build," he said.

Perhaps the most important lessons learned from animal coronaviruses are that coronaviruses are hardy, adaptable, and likely to persist in human and animal populations.

"We can expect SARS to be around awhile," Dr. Brian said. "We don't know if the epidemic will get worse or fizzle out. We just can't predict that."