New study on smallpox in monkeys reveals tactics of a killer

Results of a new study in monkeys offer scientists a rare glimpse of how, on a molecular level, the smallpox virus attacks its victims. The findings shed light on how the virus caused mass death and suffering, and will help point the way to new diagnostics, vaccines and drugs that would be needed in the event of a smallpox bioterror incident.

The study, led by David Relman, M.D., of Stanford University, is now online in the Proceedings of the National Academy of Sciences (PNAS). The research was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

“In light of today’s concerns about bioterror attacks, we have an urgent need to know as much as possible about the workings of the smallpox virus and other bioterror agents,” says Anthony S. Fauci, M.D., director of NIAID. “This new research fills in some of the gaps in our understanding of smallpox. Now we are better positioned to speed the development of protective measures.”

Related research, also published online in PNAS this week, set the stage for Dr. Relman’s smallpox study. In this work, researchers at the U.S. Army Medical Research Institute of Infectious Diseases, the Centers for Disease Control and Prevention (CDC) and Stanford University, show that cynomolgus macaque monkeys exposed to smallpox virus can develop a disease similar to human smallpox. Previously, scientists thought it impossible for the smallpox virus to sicken any species other than humans.

Following on that discovery, Dr. Relman and a separate team of researchers did molecular-level analysis of how the smallpox infection altered gene expression patterns in the monkeys’ blood cells. Dr. Relman used DNA microarrays, a tool unavailable in 1977 when naturally occurring smallpox was eradicated after a global vaccination campaign. Microarray analysis research reveals how smallpox alters gene activity in host cells under attack by the virus. It also reveals changes in levels of gene expression and expression of some proteins in the blood of monkeys when they are infected with smallpox virus. In their PNAS paper, Dr. Relman and colleagues suggest possible mechanisms by which the virus subverts host defenses. Uncovering these mechanisms gives scientists targets for developing countermeasures to lessen or block the ability of the smallpox virus to cause disease.

Experts believe that this new knowledge of how smallpox acts on cells could speed up development of smallpox countermeasures. Researchers will now be able to compare the actions of smallpox on cells to other pox viruses and use less lethal pox viruses in the search for smallpox countermeasures.

CDC has the only U.S. laboratory facility in which research using smallpox virus is permitted. However, many more labs in the United States have sufficient safety features for handling less-lethal pox viruses, such as monkeypox. If monkeypox–a pox virus less virulent in humans–proves to have molecular workings similar to smallpox, researchers could test countermeasures on it in a greater number of lab facilities, hastening the pace of research.