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.
NIAID supports research to develop animal models of monkeypox infection. Researchers will evaluate the amount of virus needed to cause disease by natural routes of infection such as inhalation, and the way in which the disease develops. These models could potentially be used to advance the development of diagnostics tools, vaccines and therapies for smallpox without employing smallpox virus. NIAID is supporting this research through its "In Vitro and Animal Models for Emerging Infectious Diseases and Biodefense" program.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
References: KH Rubins et al. The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model. Proceedings of the National Academy of Sciences DOI: 10.1073/PNAS0405759101.
PB Jahrling et al. Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox. Proceedings of the National Academy of Sciences DOI: 10.1073/PNAS0405954101.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Journal
Proceedings of the National Academy of Sciences