Insight: Research Edition

Fall 2006

Dual Task of Understanding Select Agent Physiology While Developing New Therapeutics and Vaccines a Research Challenge

Researchers at the Rocky Mountain Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (RMRCE) are charting new territory as they embark on investigations into infectious agents that have received little attention over the years. The factor creating the need for an infusion of resources into these diseases is that these agents can be turned into biological weapons.

The challenge for RMRCE researchers like Drs. Catharine Bosio and Steven Dow is that the National Institutes of Health is asking not just for basic science research, it wants research that will deliver viable treatments and effective vaccines. This applies to a lengthy list of infectious agents, many of which are poorly understood and, up until recently, have received little attention from the biomedical community due to limited threat and a lack of resources. Bioterrorism, however, is creating a new field of research into select agents that can be engineered into weapons.

“The need for vaccines is great, especially for first responders and for troops going into areas where some of these diseases, like tuleremia, are endemic,” said Dr. Bosio, an Assistant Professor in the Department of Microbiology, Immunology and Pathology (MIP) and co-principal investigator and co-investigator on several RMRCE projects. “In a bioterrorism attack with these agents, which are typically found in nature, the agents can in some cases be engineered to increase their ability to cause disease, make them resistant to current medicines, or to increase their ability to be spread into the environment.

"One area of particular concern is pathogens that can be inhaled and potentially cause more severe disease and rapid disease. We want to understand the response in the lung – how it gets rid of a pathogen and what it considers benign. There are a lot of questions that need to be answered.”

Bioterrorism agents can be separated into three categories depending on how easily they can be spread and the severity of illness or death they cause. Category A agents are considered the highest risk and Category C agents are those that are considered emerging threats for disease. Researchers with the RMRCE work with select agents in Category A and B, including Yersinia pestis, Burkholderia mallei and B. pseudomallei, Francisella tularensis and others.

“We are particularly interested in the development of new immunotherapeutic approaches for Yersinia and Burkholderia. We’ve previously developed immunotherapeutics for treatment of cancer and we now want to expand this platform to the treatment and prevention of infectious diseases,” said Dr. Dow, an Associate Professor in the Department of Clinical Sciences and MIP, and principal investigator with Dr. Bosio on the RMRCE project Role of Innate Immunity in Pulmonary Burkholderia Infection. “We are looking at innate immune responses, the body’s first line of defense against pathogens, and how we can give that a boost particularly in the lungs.”

Dr. Dow noted that the first step in creating new immunotherapies is the development of a mouse model that will allow researchers to assess immunologic responses to infection with newer agents such as Burkholderia. Much of this work will build on recent studies done in the lab to develop a mucosal vaccine against pneumonic plague (Yersinia pestis) which also are being conducted by Drs. Dow and Bosio under a separate NIH grant. After the Burkholderia infection model is established, the research team then wants to determine the role of key cytokines and signaling molecules in controlling Burholderia infection in the lungs. The final step will be assessing the ability of a novel immunotherapeutic developed in their lab to elicit protection from infection. These studies will be conducted concurrently with plague vaccine studies which will involve the development and testing of new vaccine adjuvant platforms (substances added to vaccines that intensify the immune response to an antigen).

In the Francisella tularensis study, Dr. Bosio is co-investigator with Dr. John Belisle, and they are developing proteomic techniques to identify dominant antigens that may provide a set of vaccine candidates to evaluate in conjunction with new adjuvants. The goal of the study is to develop three or four vaccine formulations that will eventually enter clinical studies.

“Many of the diseases we are working with now have long been neglected because they weren’t a major concern in the United States,” said Dr. Bosio. “For example, we see maybe 100 cases of tularemia a year in the United States but it is potentially a real threat as a bio-weapon because it is one of the most highly infective bacteria known. Just a few organisms, sometimes fewer that 10, can cause disease. With new funding from the NIH, we are exploring and learning so much about these pathogens, and we expect that what we discover here will apply to other infectious diseases that cause much suffering around the world.”