Insight

Fall 2003

Research Update

Microbiology Team Receives $7 Million to Develop Early Test for Leprosy

A team of nine Colorado State microbiologists, led by University Distinguished Professor Patrick Brennan, has been awarded two grants from the National Institutes of Health to develop early tests for leprosy based on the recently completed genome of the bacterium responsible for the disease.

The Colorado State team, which received a total of $7 million, is working with four international centers in Katmandu, Nepal; Cebu, Philippines; Rio de Janeiro, Brazil; and Medellin, Colombia, areas of the world where leprosy is still endemic.

Currently, there are no pre-clinical tests for leprosy. Diagnosis is based on physical examination for infected patches on the skin. Thanks to a successful application of multi-drug therapy, however, those diagnosed with leprosy can control the disease.

One of the few basic research programs on leprosy worldwide has been located at Colorado State University since 1980 in the Mycobacterium Research Laboratory. The laboratory, which also works to a large extent on the related disease of tuberculosis, is part of the College's Department of Microbiology, Immunology and Pathology.

Dr. Brennan's research team contributed to the discovery of the bacterial factors responsible for leprosy and the factors that can be used in an early diagnosis of the disease. For this discovery, Dr. Brennan's team was awarded an earlier grant from the National Institutes of Health.

With this current award, Dr. Brennan and colleagues have set a goal of one new early-testing tool per year of the seven-year grant. The team already is applying new tests to leprosy patients in clinical trials in Katmandu, Nepal.

Prion Research Laboratory Awarded $8 Million to Study CWD

The National Institutes of Health recently awarded an $8.4 million grant to the College's Prion Research Laboratory to study chronic wasting disease (CWD) including its mode of transmission, the potential for inter-species transmission and a possible vaccine against the disease.

The research study will focus on four major objectives: assess how CWD is transmitted among deer, develop a transgenic mouse model for CWD, evaluate the potential for inter-species transmission of CWD, and test potential strategies for a CWD vaccine.

Dr. Edward Hoover, a Colorado State University Distinguished Professor and Director of the laboratory, acknowledged that the objectives of the research are very ambitious, but that he and his collaborators are looking forward to the challenge.

"Progress in the study of this disease has been difficult because the causative agent is a protein rather than a nucleic acid-containing agent," Dr. Hoover said. "Therefore, we can't use the kind of technology we use to detect and understand viruses and bacteria.

"Additionally, the incubation period is quite long - probably two to six years in nature. For this reason, we are working with Dr. Glenn Telling at the University of Kentucky to develop a transgenic mouse model to more easily study the pathogenesis, transmission and intervention of CWD."

The team also will focus on detecting the CWD prion in body fluids and excretions of deer since, as Dr. Hoover explained, one of the most interesting and important aspects of the disease is how the infection is transmitted among deer.

Chronic wasting disease was first detected in the late 1960s and is endemic in free-ranging deer and elk in northeastern Colorado and southeastern Wyoming. More recently, the disease has emerged as a threat to ranched elk in several western states and has been found in the Midwest in areas of Wisconsin. It is one form of a group of fatal brain diseases called transmissible spongiform encephalopathies, or TSEs, which include bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans. To date there is no evidence that CWD is transmissible to humans.

Research May Help Decrease Number of Serious Infections in Medical Patients

A collaborative research project conducted by a Colorado State University veterinarian and two Boulder scientists with Rose Biomedical may lead to new medical technology for reducing the number of serious infections suffered each year by millions of both animal and human patients.

Dr. William Dernell, as associate professor in the Department of Clinical Sciences, and Drs. Steve Frank and Ammon Balaster, scientists working with Rose Biomedical in Denver, have the first study underway using a rat model. The project will test the efficacy of a new antimicrobial treatment for serious, established infections that are the result of major surgery or long-term medical treatment.

If successful in the initial study, the technology will be further tested at the College's Flint Animal Cancer Center to assess how well it works in reducing infections in dogs that have undergone limb spare surgery to remove and replace cancerous bones.

"To prolong their lives, dogs with bone cancer often require the removal of the cancerous bone and use of a replacement rod," said Dr. Dernell. "Unfortunately, about 50 percent of these dogs suffer postsurgical leg infections where systemic antibiotics may have limited effectiveness. In human cancer patients, the infection rate is between 20 and 25 percent."

Dr. Dernell explained that, in these cases, most of the infections are deep in the tissues and are of mixed origin. Additionally, most dogs that have undergone cancer surgery already have been treated with a course of antibiotics while undergoing chemotherapy. "So there is already something of a resistance to some antibiotics," Dr. Dernell added.

The new method for treating these hardy, persistent infections involves driving the antibiotic deeper into the affected tissues so that it can attack the bacteria more directly. Dr. Frank, who has spent years perfecting the technology, believes this new method will revolutionize this type of medical treatment.

The rat study model currently being used in this project simulates a previous study conducted by Dr. Dernell. In that test, antibiotic polymer beads were evaluated as a treatment for resistant infections. That study provided a very rigorous test model for antimicrobials and offers a direct comparison of effectiveness.

Dr. Dernell and his associates have applied for a grant from the National Institutes of Health to pursue additional pre-clinical studies at Colorado State and, eventually, develop a treatment application that can improve the quality and reduce the cost of healthcare.

CDC Awards Training Grant In Vector-Borne Diseases to AIDL

The Centers for Disease Control and Prevention has awarded a Fellowship Training Program grant to the College's Arthropod-Borne and Infectious Diseases Laboratory.

The grant provides almost $250,000 per year for five years to train graduate students in medical entomology, arbovirology, microbiology, and vector-borne diseases. The ultimate purpose of this funding is to improve the ability of the U.S. public health system to effectively respond to the problem of vector-borne infectious diseases by increasing the number of specialists with demonstrated field- and laboratory-based skills.

"We're very grateful to the CDC for this award. Being selected for one of these grants says quite a lot about the quality of our research, our facilities, and our scientists," said Dr. Barry Beaty, University Distinguished Professor and former head of the AIDL at Colorado State. 'This award complements the funding we just received from NIH to form, in partnership with the University of Texas Medical Branch in Galveston, an Emerging Virus Disease Unit and demonstrates the importance of this kind of research."

Dr. Carol Blair, former chair of Department of Microbiology, is co-program director on the grant, which also includes an illustrious roster of internationally recognized researchers and AIDL faculty, including Drs. William Black, Richard Bowen, Charles Calisher, Jon Carlson, Joel Hutcheson and the Director of AIDL, Ken Olson.

The more than 30 researchers at the Arthropod-Borne and Infectious Diseases Laboratory at Colorado State concentrate on the prevention, diagnosis and control of mosquito-borne encephalitis, yellow fever, dengue, Hantaviruses, parasitic diseases, and Lyme disease. Researchers at AIDL regularly collaborate with researchers at the Fort Collins laboratory of the Centers for Disease Control and Prevention - Division of Vector-Borne Infectious Diseases and the U.S. Department of Agriculture - Arthropod-Borne Animal Diseases Research Laboratory in Laramie, Wyo., which provides an unparalleled training experience in vector-borne disease for the students at Colorado State University.

The CDC grants are part of the "Healthy People 2010" initiative, which is designed to make dramatic progress in improving the health of America's population during the next 10 years.

Mycobacterium Researchers Receive $3 Million Grant to Study TB Vaccines

Drs. Ian Orme and Randy Basaraba in the Department of Microbiology, Immunology and Pathology have been awarded a five-year, $3 million grant from the National Institutes of Health to conduct a pioneering study to examine the long-term effectiveness and safety of tuberculosis vaccines. The scientists are determining if the most promising new vaccines - those proven successful in short-term studies - can remain effective over the long term and if specific vaccines could actually be damaging to the lungs over time. The team is striving to provide the first fundamental scientific information regarding pathological changes in the lungs induced by tuberculosis vaccinations.

"This has not been looked at before and is the next important step in our tuberculosis vaccine research. We know that several tuberculosis vaccines seem to be effective in the short term, but there is not a lot known about how these work at the basic pathology level," said Dr. Orme, principal investigator of the study. "However, we also are going a step further with our research to look at the long-term safety and effectiveness of TB vaccines, another area which has previously received very little attention."

The safety issue is currently of great concern to the researchers because of a newly emerging category of live vaccines derived from mutated TB bacteria. This new class of potential vaccines has great promise but also may carry big risks. Previous studies have provided no long-term safety data about these types of vaccines. With more than eight million verifiable new cases of tuberculosis each year, there is an urgent need for more effective vaccines. Recent data suggests that the current annual death rate of 3.3 million people per year due to the disease may be increasing. Nearly one-third of the world's population, approximately two billion people, is believed to be infected with TB.

The College of Veterinary Medicine and Biomedical Sciences is home to the world-renowned Mycobacterium Research Laboratory which mainly focuses on studies of tuberculosis and leprosy. The laboratory's TB-related work has been supported by more than $50 million in research grants and led to several breakthroughs in the field.

West Nile Virus Studies Released

Researchers at the College have released results from a research project that summarized the background characterization of last year's outbreak of West Nile virus in equids from Colorado and Nebraska.

"The objective of the study was to describe the equine West Nile virus cases in Colorado and Nebraska in order to better understand the progression of clinical disease, clinical signs, and clinical outcome," said Dr. Josie Traub-Dargatz, a Professor in the Department of Clinical Sciences and principal investigator on the project. "The study's results give us a clearer picture of last summer's outbreak, especially in terms of the numbers of horses affected that were unvaccinated or incompletely vaccinated as well as their survival rate."

Study results indicate:

•  The estimated case fatality rate for affected horses in Colorado and Nebraska was 28.6 percent, similar to reports from other regions.

•  The age range for equine cases was from three months to 35 years.

•  Only 13 cases in the study were fully vaccinated based on current manufacturer recommendations. Of these, the survival status of 12 is known and all 12 horses lived.

•  The most common clinical sign associated with West Nile virus infection identified in the study was an altered gait including reluctance to move, stumbling, perceived lameness, and ataxia or weakness.

The complete study report can be viewed and/or downloaded at the University's Animal Population Health Institute Web site at http://www.cvmbs.colostate.edu/aphi/activities.htm#WNV.

In a second study released in May, Dr. Traub-Dargatz's team examined the economic impact of West Nile virus on the Colorado and Nebraska equine industries. The study showed that the disease cost equine owners more than $1.25 million in 2002, and prevention costs for WNV vaccinations likely exceeded an additional $2.75 million. Colorado reported 378 and Nebraska reported 1,100 confirmed cases of WNV in equids.

"To date, no other comprehensive national or regional estimates of WNV's economic impact on the equine industry have been published," said Dr. Traub-Dargatz. "Determining the economic impact of the disease is important for prioritizing current and future research as well as management and control efforts."

The study, published by co-authors from the United States Department of Agriculture's Animal and Plant Health Inspection Service, was a cooperative effort among researchers from Colorado State University, the USDA, Colorado and Nebraska State veterinarians, and the veterinary schools at the University of Nebraska and the University of Pennsylvania. A complete copy of the report is available at www.aphis.usda.gov/vs/ceah/cahm/Equine/wnv-info-sheet.pdf.