As a PhD student at Johns Hopkins University, Horácio Frydman’s career was altered in a big way by a very small creature. In a routine experiment involving DNA staining of a fruit fly, Frydman noticed something unusual. Strange DNA seemed to be accumulating outside the nuclei of cells in a certain region of the ovary. An experienced postdoctoral researcher told him it was most likely an experimental artifact. But he pushed on, and soon found that not only was the staining real, it was actually from bacteria growing inside the fly cells called Wolbachia. His fascination with this serendipitous discovery stuck with him.
Today, as an assistant professor of biology and the associate director of the Vector Transmitted Infectious Diseases Core at the National Emerging Infectious Diseases Laboratories at BU, Frydman works to reveal the unknown characteristics and mechanisms of these enigmatic bacteria—research that will help scientists understand new strategies for preventing the spread of diseases like malaria, West Nile, and dengue fever.
Wolbachia are remarkably prolific intracellular bacteria found in almost 70 percent of insects and several parasitic worm species worldwide. Depending on the host and bacterial strain, effects of Wolbachia infection can range from pathogenic to benign. The bacteria can drastically reduce the life span of a host or increase reproductive success. Because Wolbachia are transmitted from a mother through her eggs, these manipulations usually evolve to favor infected mothers, ensuring the continued success of the bacteria.
The ability to thrive in and manipulate insect populations makes Wolbachia attractive to scientists researching diseases transmitted by them. Researchers know that a specific strain of Wolbachia isolated from fruit flies can reduce the life span of mosquitoes by half—enough to prevent the spread of dengue fever, transmitted by older mosquitoes. Scientists also found that Wolbachia-infected mosquitoes are less likely to carry diseases like malaria and West Nile, due to a heightened immune system in the presence of the bacteria.
“It was a side project for me as a PhD student, but when I realized that the unusual DNA staining was these bacteria, I became very interested,” recalls Frydman. “I wanted to explore the public health importance.” As a native of Brazil, Frydman cares deeply about these diseases, which are prevalent in tropical areas. “But this is an issue even for the Boston area,” he notes. “We have eastern equine encephalitis, we have West Nile virus. Wolbachia can be used as a tool to control these diseases.” The problem, he says, is that no one knows how the bacteria will spread in nature and manipulate the host’s biology.
Luckily, the serendipity that marked Frydman’s entrance into Wolbachia research has continued. During Frydman’s first months at BU in 2007, Danielle Desjardins, an undergraduate research assistant, made a curious observation while conducting a simple experiment. Wolbachia-infected Drosophila mauritiana, a species of fruit fly related to the more famously studied D. melanogaster, laid almost four times as many eggs as uninfected flies. Eva Fast, then a first-year graduate student, continued the project. Although she had no previous experience with Wolbachia, after four years of hard work and with the help of Michelle Toomey, then an MA candidate in biology; Eric Kolaczyk, a statistician in the math department; and other members of the lab, their research was published in Science in 2011.
They found that Wolbachia inhabit cells in a region of the fly ovary known as the germline stem cell niche. The bacteria’s presence vastly increases the rate of division of the nearby stem cells that produce eggs. The bacteria also decreased the amount of programmed cell death, which helps control the rate of reproduction in developing eggs. These effects, in combination, led to a massive increase in fly fecundity. “This was the first time that a mechanism explains how Wolbachia manipulate the reproduction of their host,” says Frydman. “Nobody knew the cellular mechanisms before.”
Frydman believes this work, and his lab’s future research, will reveal valuable insights into how Wolbachia interact with the hosts, including mosquitoes. Currently, Frydman and his students are working to identify the molecular mechanisms of these interactions. “Our idea is to take what we find in flies—including signaling pathways and genes—and then confirm if they are also relevant in mosquitoes infected with Wolbachia,” says Frydman. His lab is also actively working to identify the stem cells and stem cell niches in the mosquito ovary.
Scientists around the world are developing Wolbachia-based strategies to control diseases. “Understanding the fundamental biology behind how Wolbachia interact with the host at the cellular and molecular levels is important for improving these strategies and developing new ones,” he says, “but there is a lot of basic research that needs to be done.”
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