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Getting to the Bottom of Influenza with Comparative Medical Research

InfluenzaUnlike many of our faculty members, veterinarian Nicole Baumgarth does not treat cats, dogs or horses.

Instead, she is unraveling some of the mysteries of the influenza virus, which causes serious and sometimes fatal disease in people and animals.

Using the mouse as a model, scientists in the Baumgarth lab attempt to measure what happens when influenza strikes. New knowledge may help scientists develop more effective vaccines.

"I'm an immunologist," Baumgarth states. "The question I hope to answer is 'What does the immune system do to protect itself from or rid itself of infection?'"

Flu viruses are particularly fascinating to study, she says. "The influenza virus offers unique things to study. Flu infects its host and three days later, it is at its peak. The host does a really good job fighting the infection. Once the immune system kicks in, that mouse is protected for life from that form of influenza. If a vaccine could be developed to produce as good a response as a real infection, we would have wonderful protection."

"Unfortunately, for us, it takes 5-7 days to get a fully effective immune response—the virus has almost gone by the time a specific immune response kicks in. The host does everything right, but the virus is too fast. The virus jumps from one host to another."

Mice and people can recover from the flu and remain immune to one or more strains. Full human immunity to the influenza family of viruses is tricky. "The virus can change frequently, and even a small change helps it avoid the next immune response," Baumgarth explains.

Baumgarth's focus is a subset of cells called B cells that produce antibodies to the flu. Among those B cells is a smaller subset (B-1) that produce natural antibodies that are not as specific as those generated by most other B cells. These antibodies can therefore protect from many different strains of influenza. One focus of her work is to determine how this B cell subset is regulated to produce these antibodies and how it could be triggered by a vaccine to participate in the immune response.

Another focus is on understanding how the other very specific B cell responses can be induced to make protective antibodies to influenza. "We [humans] virtually always respond. We can trace what is happening or not working. Since we started this work, we have been looking earlier and earlier in the immune response."

"The most exciting result in the past 3-4 years," Baumgarth says, "is that we have identified a signal that the B cells receive early after the infection—the first day."

In an article published in April 2006, Baumgarth, and her co-authors describe this effect. "We know that the B cell receives a signal from a cytokine—a hormone called interferon that is produced in response to influenza and other viruses." This signal is important because a mouse that lacks receptors to interferon does not make a very good B cell response.

Though the interferon signals arrive in the B cells on Day 1, the immune response cannot be measured easily until around Day 5. Baumgarth says, "Our next research questions are 'What happens between Days 1 and 5' and 'What does this signal give to the B cell?'"

To that end Baumgarth and her colleagues have developed a number of techniques to identify and measure the responses of the very small number of influenza virus-specific B cells present on those early days of the infection. One technique is to generate small pieces of influenza and attach them to a fluorescent-color tag. These virus pieces will bind only to B cells that are specific for the virus. The color tag can be used to count the cells. Once identified by that technique, researchers can then study the cells' responses.

Baumgarth's work relies on laboratory animals to mimic human diseases and responses. "It's really valuable to work with the whole animal model rather than at the tissue or molecular level. Only the mouse can give us information at this level of detail." There is no other way to really understand of how many different components of the immune system work together to provide protection from an infection.

"The mouse is more efficient and inexpensive than other animal models," she adds. "But the cost of buying, rearing and keeping mice is my single highest expense. There are also ongoing responsibilities of saving mice for future, similar experiments."

The lab uses 8-10 strains of genetically altered or "knockout" mice. Most came from collaborators around the world. "In searching for reagent to make a mouse that does not express the interferon receptor on B cells but has it on all other cells in the body, I learned that a German scientist had already made the type of mouse I needed," Baumgarth explains. "With his cooperation, I have been able to save about three years of work that it would have taken to develop that mouse type."

To make it easier for scientists to share their genetically altered mice, the NIH has a "resource sharing" component associated with each grant. The institute is also supporting mouse repositories (see related stories of July 11 and September 7

Baumgarth is based at the Center for Comparative Medicine, where veterinary and medical school faculty investigate diseases shared by animals and humans.

Recent citations on Pub Med