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A few bacteria are especially adept at stealing genetic material from other bacterial species and incorporating those foreign genes into their own machinery. In a new study, St. Jude researchers have gained insight into how pneumococcus, the primary cause of pneumonia, uses a particular piece of stolen genetic material to render it more virulent.
The research is part of the hospital’s ongoing effort to develop affordable and effective pneumonia vaccines for children in developing countries. This is an especially critical effort, given that pneumonia causes more than 2 million deaths a year in children worldwide—more than AIDS, malaria and measles combined.
The St. Jude researchers sought to understand how pneumococcus regulates a stolen piece of genetic material that enables the bacterium to construct a structure called a pilus. The pilus is a long, hair-like appendage that the bacterium uses to reach out to human cells that it infects.
“Even though pneumococcus is very common, until recently no one had realized that it could develop this pilus to reach out and touch a human cell,” said Elaine Tuomanen, MD, Infectious Diseases chair and senior author of a report on this work that appears in the July 2008 issue of Infection and Immunity. “Oral streptococci, which are normally in the mouth and throat, have the pilus ‘genetic package,’ and we believe pneumococcus picked it up in the back of the throat. We decided to look at how the bacterium figures out how to use that package.”
The scientists hypothesized that the imported pilus genetic package had adapted to a preexisting set of molecular controls in its new host environment. In their experiments, the researchers genetically altered strains of pneumococci to shut down those controls to see whether pilus development was affected.
Those experiments established that pneumococci do use those controls to regulate the pilus locus. Furthermore, the experiments with mice revealed how pneumococci use the pilus locus to improve their ability to infect lung cells.
“When bacteria attack the lung, there are two steps they need to do to establish pneumonia,” Tuomanen said. “They need to stick to lung cells, and they also need to invade the lung cells. Our experiments were designed to separately test those two steps, and we established that the pili are not used for adhesion, but for invasion, which was not understood before.”
While the findings help scientists understand the basic machinery of pneumococcal infection, Tuomanen said, the results also indicate that pilus is not a good candidate for a new vaccine against pneumonia. Such vaccines consist of a mix of bacterial proteins that can be administered to children to trigger their immune systems to battle a broad array of pneumococci strains.
“So far, only 20 percent or so of the clinically important strains of pneumococci have developed this trick of producing the proteins for making pili,” Tuomanen said. “In creating vaccines, we want to use proteins that occur in a wide variety of bacterial strains. These pili-related proteins are not prime candidates. So, we can now concentrate on other proteins that we know are expressed almost universally by pneumococci, and that we can put into a vaccine.”
The goal ultimately, Tuomanen added, is for St. Jude and its collaborators to produce pneumococcal vaccines that will have a profound impact on the disease worldwide.
“Current vaccines used in the developed world cost over $100 a dose and are limited to protecting against perhaps 10 to 15 types of pneumococci,” she said. “But that price is far too high for developing countries, and there are 90 types of pneumococci out there.” However, St. Jude and its collaborators have already identified bacterial proteins that occur almost universally in pneumococci and that could be the basis for a vaccine inexpensive enough to be used in developing countries, Tuomanen said.
Vaccines based on these proteins will be produced in the Children’s GMP, LLC, facility, a sophisticated biomedical workshop for making high-quality vaccines, drugs and other biological products. The GMP’s capabilities enable researchers’ discoveries to be quickly brought to clinical trial.
Other authors of this study include Jason Rosch, Beth Mann and Justin Thornton, all of Infectious Diseases; and Jack Sublett, Genetics and Tumor Cell Biology.
This work was supported in part by the National Institutes of Health and ALSAC.