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Pictures of Health Spring 2005
Small is Powerful
Tiny, potent threats —viruses— are the targets at the new Institute for Molecular Virology that brings together researchers from across the U.
By Andrew Bacskai
Some of humankind’s most formidable opponents are ultramicroscopic in size. They’re viruses, infectious agents so small they’re invisible to everything but the electron microscope-aided eye. Viruses, whose name is derived from the Latin word for poison, infect their living hosts by invading their cells, releasing their DNA or RNA inside, and forcing the cells to produce thousands of new viruses.
Individually, such viruses as HIV, smallpox, influenza, and Ebola can overwhelm the human body—and potentially overtake significant segments of the human population. Collectively, they pose a constant and ever-changing threat to public health.
“The greatest fear among people like myself is letting the AIDS pandemic, for example, continue on in parts of the world,” says Louis Mansky, professor of oral science in the School of Dentistry who also holds an appointment in microbiology in the Medical School. “One of the worst-case scenarios is that these viruses can evolve to the extent that they become more pathogenic or more transmissible among humans”
Though it’s only been about 100 years since viruses were first discovered, virologists have mounted a significant counterattack over the past several decades. Smallpox, for example, now exists only in well-protected laboratory vials. Meanwhile, powerful antiviral drugs have helped undercut the lethal capabilities of HIV in North America and Western Europe.
Trouble is, virology remains a largely decentralized discipline. At the University, for example, “virologists have populated departments throughout the University in a scattered, noncoherent way,” says Michael Murtaugh, molecular biologist in the School of Veterinary Medicine. He attributes this arrangement, in large part, to the fact that virology is a relatively new field.
“How do you study viruses?” he says. “You study them using the traditional methods: biochemistry, structural biology, molecular biology, cell biology, and immunology. Those all are different disciplines. So if you want to have a center of excellence in virology at the University of Minnesota, you cannot do it in any of the existing departments or divisions, because virology requires the interaction of all those disciplines. The interaction could make the whole more than the sum of its parts.”
That’s why Mansky, who was recruited from Ohio State University, began developing a new Institute for Molecular Virology (IMV) upon his arrival in December 2003. “The idea of this institute was to bring together people across the Academic Health Center who do virus-related research,” says Mansky, director of the IMV, which is housed in the School of Dentistry. The IMV’s researchers are working towards or at the molecular level, which he describes as ground zero—the place where virus-related investigations intersect one another. The goal of the institute, he adds, is to encourage researchers from an array of disciplines to develop meaningful interdisciplinary collaborations that could potentially lead to new discoveries and, ultimately, more potent diagnostics and therapies.
“There is a general belief, certainly among federal agencies like the National Institute of Health, that this is the future of biomedical research: being able to work on complicated problems that necessitate having specialists from many disciplines working together, trying to blaze new frontiers that haven’t been challenged before,” Mansky says.
To date, the IMV includes faculty from the School of Dentistry, the School of Public Health, the College of Veterinary Medicine, the College of Pharmacy, and the Medical School. These researchers are connected through monthly meetings, in which they update colleagues on their current projects, as well as through biweekly discussions, monthly seminars, and an annual symposium.
IMV researchers are investigating 16 topics, including AIDS and HIV, emerging viruses and antiviral drugs, and drug resistance. A sampling of IMV research projects follows.
Obstructing HIV transmission
Microbiologist Peter Southern developed an experimental system in which he and his colleagues can reconstruct HIV transmission, primarily from a man to a woman. Southern’s lab is one of the few in the country to work with a system based on human tissue— namely, cervical and tonsil tissue. And though he concedes that researchers have long known how HIV is transmitted, he says that human behavior is enabling the virus to continue to thrive, especially in such areas as sub-Saharan Africa and parts of Southeast Asia.
“Condoms work wonderfully well; they provide an impermeable barrier between the infected male and the susceptible female. But in much of the developing world, there is a tremendous male prejudice against the use of condoms,” he explains. “So even though the basics of transmission have been known for 20 years, our work is still important. We are trying to understand the cellular and molecular processes that are involved. Why? So that someone … can look at our basic findings and develop some type of inexpensive, heatstable, topical agent that women could use discreetly to protect themselves from transmission.”
Protection against PRRS
Investigators in Murtaugh’s lab are focused on pig immunology. In one project, researchers are examining the immune response of pigs to Porcine Reproductive and Respiratory Syndrome (PRRS), a viral disease that suddenly appeared in herds throughout the United States and Europe in the late 1980s. In pregnant pigs late in gestation, PRRS can cause the mothers to have abortions or to give birth to weak offspring that live only a few weeks. In younger animals, the virus can cause pneumonia. “PRRS has been the most important disease of pigs throughout the world, pretty much since it first appeared,” Murtaugh says. He explains that, for farmers, treating infected herds and sustaining high numbers of fatalities can be financially devastating. “This is a disease that destroys family farms. Farmers lose their livelihoods.”
Though much about the virus remains a mystery to researchers, investigators in Murtaugh’s lab have learned that pigs’ innate immune response—which should be triggered immediately to protect the animals against viral invasion—doesn’t react to PRRS. “It’s a stealthy virus,” he says. By continuing to develop a better understanding of pigs’ immune response to the virus, Murtaugh hopes his lab’s findings can contribute to better diagnostics and more powerful prevention methods. “If we understand the mechanisms that lead to the pig getting rid of most of the virus, and if we know how to measure that, then we can start thinking about more effective control and prevention strategies,” he says.
Search for the cure
Like Murtaugh, Pamela Skinner’s research focuses on immune response, only she’s examining the anti-viral immune response to HIV in human tissues. More specifically, Skinner, a researcher in the Department of Veterinary and Biomedical Sciences, is studying virus-specific CD8-positive T cells in tissues of HIV-infected individuals. The primary job of these T cells, she explains, “is to find virusinfected cells and kill them.”
Skinner’s lab, which excels at identifying virus-specific CD8 T cells, collaborates with renowned AIDS researcher Ashley Haase, Regents Professor and head of microbiology, whose lab is adept at labeling virusinfected cells in tissues.
“Our broad goals are to understand HIV pathogenesis [i.e., disease development], and then to also understand what the correlates are of a protective vaccine,” Skinner says. “It’s thought, and at least we’d like to believe, a successful HIV vaccine would induce a very large antigen-specific CD8 T cell response.”
Likewise, the activity in Mansky’s lab is aimed at producing findings that could contribute to more effective HIVintervention strategies. “A major theme that we study is trying to understand how HIV mutates and evolves,” Mansky says. The high mutation rate in the virus, he explains, enables it to develop resistance to the various drugs prescribed by clinicians. “In order to develop a new drug, you have to understand enough at the molecular level about the drug’s target,” he says. “We do all the detailed work that’s necessary to identify the new targets that you can develop new antiviral drugs against.”
Ultimately, Mansky adds, “I’d like to purposefully put myself out of business. The goal is to make AIDS no longer a public health problem. Then I’ll just move on to another virus—there’s always something out there.”
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