STANFORD, Calif. - The tiny fruit fly has a lot to teach humans. Researchers at the Stanford University School of Medicine have found for the first time that flies' primitive immune systems may develop long-term protection from infection, an ability previously thought impossible for insects.
The findings could have implications for new ways of developing human vaccines, especially for people with compromised immune systems.
The evidence that a fruit fly's immune response can adapt to - or retain memory of - an earlier infection contradicts the long-held dogma that immune memory cannot exist in invertebrates such as insects. Such memory of a specific pathogen, known as adaptation, is supposed to be a hallmark of the higher-level immune system response of humans and other vertebrates.
The Stanford work raises the possibility that humans could make use of this rudimentary immune response if their higher-level system is crippled. "It's a springboard to looking at the immune system in a whole new way," said David Schneider, PhD, assistant professor of microbiology and immunology and senior author of the study, which will be published in the March 9 issue of Public Library of Science-Pathogens.
One of the two arms of the immune response in higher organisms is similar to that of flies. This arm is known as innate immunity, and it is thought to be a primitive first-line, nonspecific response to a pathogen "invader." The other arm found in higher organisms is adaptive immunity, which has a memory that retains an internal record of contact with an invader and - employing T and B cells - springs into action once it encounters the same invader again. This adaptive immunity explains why a vaccine provides protection.
"AIDS patients are like fruit flies in the sense that they don't have properly functioning T cells," said Schneider. "If there is anything we could do to make their remaining innate immunity better through adaptation, that would be really helpful."
Harnessing the potential power of adaptation in the innate immune system might also be a boon in the body's defense against bioterrorism or disease pandemics. "The B and T cells of the adaptive immune system take a long time to react," said Schneider. "But you might be able to speed things up if you could snort something up your nose that would make your innate immune system ready to fight."
While inviting novel ways of thinking about future vaccines and treating AIDS patients, the new finding immediately stirs up the field of insect immunology. Existing publications about the fruit fly's immune system explicitly state that it has no memory, and no ability to make specific long-term changes prompted by its exposure to pathogens. Because immune memory was defined as nonexistent, no one ever did the experiment to question whether the fly's immune system could adapt.
Then graduate student Linh Pham arrived in Schneider's lab. She was interested in pushing the boundaries of the assumptions of the innate immune system's limitations.
In the past decade or so, work done on fruit fly immunology has always been done on a fly infected only once - and that's not how things happen outside a lab, where a fly would be continually exposed to microbes. Pham thought to ask what happens when the flies encounter a microbe a second time.
Pham found a bacterium - Streptococcus pneumoniae - that infected the flies but didn't kill all of them. "I liken my work to the first vaccination experiments," said Pham, who is first author of the study. She essentially vaccinated over a million flies, typically doing 7,000 in a day, in numerous experiments. In a key experiment, she injected some flies with killed bacteria and others with just saline solution. She waited a week, then reinjected both groups with what should have been a lethal dose of live bacteria. Then she calculated the percentage of how many survived, compared with the flies that been injected only with saline.
"I didn't think the results would be so clean-cut," she said. Within two days, the second dose killed almost all of the flies that had initially received just saline solution. Those that had been vaccinated lived just as long - about one month - as a separate group that had not been infected.
To ensure it wasn't a fluke of the bacterium she chose, she tested other organisms. She identified a fungus that infects fruit flies in the wild, Beauveria bassiana, that elicited a similar protective effect. "It was really easy to show the adaptation part," she added. "Getting to the mechanism was the complicated part."
In the study, the researchers conclude that a much-studied receptor called Toll is involved, as are other processes. Pham is now teasing apart the finer aspects of how the fruit fly protects itself against S. pneumoniae.
Schneider and Pham said they hope their work encourages the search for a similar adaptive response in the innate immune systems of humans or other vertebrates. "One of the things that I thought was really cool about this work is that it might be a way to develop a vaccine that modulates the innate immune system," said Pham. "Of course, we are cautious about hoping for this."
In addition to Schneider and Pham, postdoctoral scholars Marc Dionne, PhD and Mimi Shirasu-Hiza, PhD, contributed to the studies. This work was supported by grants from the National Institutes of Health, the Irvington Institute and the National Science Foundation.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
Journal
PLoS Pathogens