SARS  pg. 2

We were lucky with SARS, Denison says. Despite its high pandemic potential, the SARS coronavirus also had an Achilles heel that made it succumb to the infection control barriers erected against it. The next time around, we might not be so lucky.

Crown of spikes

In images from the electron microscope, coronaviruses look like the suns of preschool drawings—large circles surrounded by crowns of smaller dots. The crown, formed by the “spike” protein on the viral surface, gives the family its name.

Inside these spike-covered spheres is the coronavirus genome, one long chain of nucleic acids. While most organisms have DNA as a genetic material, coronaviruses—and other viruses including HIV and influenza—use RNA, a fact that makes them prone to mutation.

The coronavirus genome, the largest-known RNA molecule, is translated in infected cells into a replicase polyprotein, which is snipped into smaller proteins that together mediate all of the different steps of making new viruses.

The replicase polyprotein captured Denison’s interest nearly 20 years ago. He and Stanley Perlman, M.D., Ph.D., professor of Pediatrics and Microbiology at the University of Iowa, were the first to identify coronavirus proteins that were required for the virus to reproduce. Using tools such as monoclonal antibodies, antibodies made in the laboratory to recognize specific targets, Denison has continued to work toward a complete understanding of what the proteins are, how they’re lined up within the larger polyprotein, and how they’re cut apart.

“Sometimes it’s been like working on a jigsaw puzzle where all the pieces are square, and they’re all black, and I’m in a closet with the lights turned off,” Denison muses. Adding to the difficulty, he says, has been the need over the course of his career to explain why he would choose to work on mouse hepatitis virus, one member of the coronavirus family. He recalls hallway conversations with colleagues that went something like: “You’re a smart guy, Mark, why don’t you study a different virus?”

It turned out that those studies were critical.

“When the SARS epidemic hit, Mark was among the first to realize that of the coronaviruses, SARS was most like mouse hepatitis virus,” says Barton Haynes, M.D., director of the Duke University Human Vaccine Institute, and leader of the Southeast Regional Center of Excellence for Emerging Infections and Biodefense. The consortium of six universities, including Vanderbilt, is charged with developing the next generation of vaccines, drugs and diagnostic tests against emerging infections such as SARS, and for defense against organisms such as smallpox that might be used in bioterrorist attacks.

Denison “had already made many monoclonal antibodies against (mouse hepatitis virus) replicase,” Haynes says. “Remarkably (they) reacted with SARS, and Mark had the first SARS monoclonal antibodies in the world. He continues to make major contributions to our understanding of SARS pathogenesis, and is already regarded as a world leader in the field of both coronaviruses and SARS in particular.”

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