The crystal structure of reovirus sigma 1 protein, left, shows that sigma 1 has the same basic fold and overall morphology as the fiber protein of adenovirus, which belongs to an unrelated virus family.
Study finds evolutionary link between two viruses
The collaborative teams includes, left to right, Dr. James Chappell, Dr. Andrea Prota, Thilo Stehle, Ph.D., and Dr. Terrence Dermody.
Researchers at Vanderbilt University Medical Center, in collaboration with Harvard University Medical Center, have linked two different virus families, reovirus and adenovirus, which may lead to the development of new antiviral drugs and a better understanding of the strategies microbes use to dock and internalize inside cells to begin the process of infection.
Dr. Terence Dermody, professor of Pediatrics and associate professor of Microbiology and Immunology, and Harvard structural biologist, Thilo Stehle, Ph.D., led the study that has revealed remarkable similarities in the attachment proteins of two quite dissimilar viruses, suggesting a common ancestor.
The five-year study began with a phone call from Stehle to Dermody, asking the Vanderbilt researcher if he would like to work with Stehle’s group in solving the structure of the sigma 1 protein.
“I was thrilled that we would have attracted the attention of a structural biologist of Thilo’s caliber,” Dermody said.
Dermody then contacted Dr. James Chappell, who had been Dermody’s first graduate student and who is now back in the lab as a clinical pathology resident. Chappell was enthusiastic about trying to express the protein and purify it in an attempt to crystallize it and solve the structure. So, the Vanderbilt team of Dermody and Chappell began the collaboration with the Harvard team of Stehle and his post-doctoral fellow, Andrea Prota, Ph.D.
Dermody’s lab has an interest in determining how viruses cause disease in the nervous system, and specifically how one virus may cause a sore throat while a different virus may incapacitate a patient with hepatitis or encephalitis. A key determinant of the different cell selection within the host is the attachment protein.
Some viruses resemble spherical objects with thin protein fibers that protrude from the sphere and are used to attach to the surface of the cell by binding to specific receptors. The cell can become infected if the viral attachment protein can bind a particular cell-surface receptor. For reovirus, the attachment protein is known as sigma 1.
The process to solve the sigma 1 structure, expected to take a year or two, stretched into five years as conditions were modified to generate the right constructs to facilitate the expression of the protein and involved the intricate cloning of small pieces that could be expressed and purified.
When Stehle visited in January 2001, Dermody and Chappell had succeeded in expressing enough protein to induce crystal growth. Stehle assisted with the last purification steps, returned to Boston with the purified protein and was successful in producing crystals and solving the structure by mid-April 2001.
Dermody describes the crystal structure of sigma 1 as stunning.
Although the two viruses are vastly dissimilar, the attachment protein of reovirus shares a striking resemblance to that of adenovirus. Reovirus has a completely different genome and replication program than adenovirus. The ubiquitous reovirus infects all mammals but rarely results in disease. Adenovirus, however, is a significant human pathogen and can cause disease in both children and adults, such as respiratory, ocular, and intestinal infections. Yet, their attachment proteins are virtually identical, suggesting that at some point, the attachment protein or the attachment strategy used by adenovirus and reovirus must have been shared by a common ancestor.
“This was a very unexpected finding since these two viruses are members of unrelated virus families,” said Dermody.
As exciting as these discoveries are for the field of biology, Dermody said there is also anticipation that this new knowledge could be applied to inhibit some of the viral attachment and internalization processes.
The National Institutes of Health and the Elizabeth B. Lamb Center Pediatric Research funded the study and the results were published in the January 2002 edition of the European Molecular Biology Organization (EMBO) Journal.