A DEADLY FOE
UTSA scientists seek vaccine against a simple but virulent life-form
Bacteria may be one-celled creatures, but they can become deadly when cultivated into bioweapons. Microbiologist Karl Klose and a team of scientists are working to develop vaccines against Francisella tularensis, one of the most lethal bacteria being studied for use as a biological warfare agent.
Six years after the attacks of Sept. 11, some experts believe it’s not a question of whether there will be another attack, but a question of when. As more soldiers are deployed in the global fight against terrorism, scientists at UTSA and other research facilities around the country are quietly focusing their microscopes on the “smallest” of threats—bacteria that can be used as biological weapons.
One-celled creatures may be the simplest forms of life, but they can become deadly when developed into an aerosol and used for bioterrorism, says Professor Karl Klose, director of UTSA’s South Texas Center for Emerging Infectious Diseases.
Funded by two awards from the National Institute for Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, UTSA researchers are working to help develop vaccines against Francisella tularensis, a bacteria that causes the disease tularemia. Klose, a professor of microbiology; Judy Teale, a professor of immunology; and Bernard Arulanandam, associate professor of immunology, are involved in the tularemia projects.
What makes their work especially important is that Francisella tularensis is one of the most lethal bacteria being studied in laboratories as a biological warfare agent. It is comparable to anthrax and the plague, Klose says.
What is tularemia?
Tularemia is a rare disease found in nature in small mammals, including rabbits, hares and rodents. Most people who contract the disease are infected when they handle the skin or meat of a diseased animal and the bacteria enters their body through a cut on the hand. Other common ways to get tularemia include eating infected meat, drinking contaminated water or being bitten by blood-sucking insects such as ticks, deerflies or mosquitoes that have had contact with infected animals. Still, tularemia, also called rabbit fever or rabbit skinner’s disease, is not easily acquired.
“Tularemia is not very dangerous if acquired by the usual route,” Klose says. “People are very likely to survive, and the disease is treatable with antibiotics.”
Tularemia, however, is much more lethal when the bacteria are inhaled. In aerosol form, it would take only 10 to 15 organisms to cause disease, according to the NIAID. The disease progresses rapidly, is difficult to diagnose because it is so rare, and has a mortality rate of about 30 percent if not treated with antibiotics, Klose explains. This, coupled with the bacteria’s ability to survive in nature, makes it an even more suitable candidate for biological warfare.
The idea of using bacteria as a weapon is not new. According to the Centers for Disease Control and Prevention, historians estimate that more than 200,000 Chinese were killed in germ warfare experiments before World War II.
“The Japanese experimented on Chinese [prisoners of war] during World War II,” Klose says. “The U.S. and Soviet Union did lots of research on biological weapons during the Cold War. We stopped our research in 1973, when President [Richard] Nixon signed an agreement with the Soviets to stop all bioweapons work and the U.S. destroyed its stockpile at that time, but the Soviets continued with their work until the Soviet Union collapse in the late 1980s.”
Friend or foe?
What makes airborne tularemia so fascinating to researchers is its deceptiveness. “When Francisella bacteria first enter the body, they are not eliminated by the body’s natural defense system,” Klose says. Like an enemy hiding in a Trojan horse, they turn deadly once accepted into the fold.
Normally, when bacteria enter the body, macrophages, a type of white blood cell, are the first line of defense. “The macrophages engulf the invaders and destroy them, then scour the body looking for more,” he says. “Then, they teach the body that the invaders are bad and help the body develop immunity.”
But that doesn’t happen with tularemia. Instead, the macrophages engulf the bacteria, but don’t kill them. As the macrophages patrol throughout the body, the tularemia breeds inside of them. Then the macrophages burst, spreading the tularemia to distant areas, where they cause widespread infection.
“What we want to find out is how does tularemia prevent itself from being killed by macrophages when it enters the body,” Klose says. “We’ve identified certain genes that play a part in the process, but we don’t yet know what these genes do. Once we figure it out, we want to develop potential vaccine candidates.”
Because of the work’s deadly implications, access to organisms for research is under tight control, he adds.
Scientific teamwork
The two NIAID awards given for UTSA’s tularemia research have one goal: to identify potential vaccine candidates to work against the disease. One is a program project grant to conduct basic research on the organism, while the other is part of a large government contract involving three universities and two companies.
The first grant was awarded in July 2005. The $6.4 million, five-year project is made up of four interdependent projects conducted by Klose, Arulanandam and Teale, as well as Michael Berton, a microbiologist from the University of Texas Health Science Center at San Antonio (UTHSCSA).
Klose studies the organism to identify the genes responsible for its ability to cause the disease. Inactivating these genes in tularemia converts them from dangerous to benign organisms, which then become potential vaccine candidates. Klose then passes them along to Arulanandam. “I am studying which of the vaccine candidates gives us the best immune response and protection,” Arulanandam says. “We have already tested some of them, and some look very promising.”
Meanwhile, Teale’s research focuses on the mechanisms that the bacteria use to avoid being killed by the body’s natural defenses, while Berton focuses on the body’s natural defense system to find out why the body does not recognize tularemia as a dangerous invader.
The second grant, awarded in August 2005, is part of a large, five-year government contract to produce tularemia vaccine candidates. “This is a more focused approach involving a national consortium of scientists with the goal of producing a tularemia vaccine within five years,” Klose says.
He and Arulanandam are working on the $1.9 million project. “We have a list of targeted antigens that Dr. Klose will mutate, then I will take those and test them in the lab,” Arulanandam says.
Research infrastructure
One of the reasons UTSA is able to conduct this type of research is an assortment of new facilities that did not exist three years ago. The 227,000-square-foot Biotechnology, Sciences and Engineering (BSE) Building on the 1604 Campus, which opened February 2006, is UTSA’s biggest building and one of the largest research facilities in the UT System.
On the third floor of the BSE is Klose’s biosafety level 2 laboratory used for nonvirulent, but high-security, research. He and Arulanandam also share a 900-square-foot BSL-3 lab to study the highly infectious forms of tularemia, work that requires the researchers to use respirators and wear special head-to-toe suits made of an impervious material.
“In the BSL-3 lab,” Klose says, “all the work is performed in biosafety cabinets, and there are redundant measures in place so there is no possibility that anyone becomes infected.” Anyone working in the labs has to have FBI clearance and undergo safety training. The labs are under high-level surveillance by the FBI and the CDC, as well as by UTSA’s safety office and police department.
The $10.6 million, 22,000-square-foot Margaret Batts Tobin Laboratory Building, which opened in 2005 on the 1604 Campus, houses a second BSL-3 lab that Teale is using for her tularemia research. In addition to the joint project with Klose and Arulanandam, she is principal investigator on a separate National Institutes of Health research program to study the pathogenesis of tularemia in the elderly. It is well known among researchers and health care personnel that those aged 65 and older have higher death rates from severe respiratory infections. Teale’s research is designed to determine whether older people are more susceptible to tularemia. “This is critical so that treatments can be developed that also work for people with weaker immune systems, such as the elderly or persons whose immune systems have been compromised,” Teale explains.
Student research
In addition to the scientists, two Ph.D. graduate students are working on the tularemia projects. They receive the same safety training and must pass the security training, Klose says.
In fall 2005, when Stephen Rodriguez first entered the cell and molecular biology Ph.D. program, he conducted a small project in Klose’s lab working with novicida, a form of tularemia harmless to humans. Now, he is conducting his Ph.D. thesis research using the more virulent form of the bacteria.
Before selecting UTSA for his graduate work, Rodriguez looked into programs at several universities. “I wanted to see which programs had a sense of purpose,” he explains. “With some of them I didn’t see it, but with Dr. Klose, I got that feeling of purpose right up front.”
Another student involved in the research is Jeff Barker. He is working on a doctorate in microbiology at UTHSCSA, but followed Klose to work in the UTSA lab when the professor came to the university in 2004. Like Klose, Barker is studying which genes make tularemia so deadly. “We have the potential for creating a vaccine that could be approved by the [Food and Drug Administration] and used by the military,” Barker says. “It is incredible to actually see results and, as a graduate student, to actually see that a product may come from your work.”
Lab work, Barker says, is the reason he got into the field. “I get to discover something new each day that no one else knows. I get to come up with new ideas to discover what makes these things tick.”
Klose likes mentoring his graduate students almost as much as he enjoys the research. There’s the constant thrill of discovery, he says, and the idea that he’s training the scientists of tomorrow.
“There is a critical need for people trained in biodefense in order to protect the American public,” Klose says. “New infectious diseases are constantly popping up. For example, five years ago, many people had never heard of anthrax, West Nile virus or SARS. We’re training the next generation of scientists who can respond to new threats and create the treatments and cures for future generations.”
— Rosanne Fohn
Illustration by Stephen Durke