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NIH-funded project gives undergraduate and graduate students hands-on roles in studying how the immune system responds to influenza

When Adeline Shanahan arrived at the University of Maine, she knew she wanted to get involved in research. 

Her interest in the immune system was also personal: her mother is immunocompromised, an experience that helped influence Shanahan’s decision to study molecular and biomedical sciences.

Now entering her sophomore year at 91����, Shanahan is already contributing to influenza research in the laboratory of Benjamin King, associate professor of bioinformatics.

“I thought it would be really cool to be in a lab that works with the immune system,” said Shanahan, also a student in 91����’s Honors College. “It was really important to me to be able to have that opportunity.”

King recently received 91����’s first National Institutes of Health R16 award, providing $400,000 in direct funding over four years to study whether a system in the body best known for regulating blood pressure also affects how the immune system responds to influenza.

For King, the project has two equally important parts.

“One is about the research, and the other really important component is providing research learning experiences to undergraduates in particular,” King said.

An unexpected connection

Influenza remains a persistent public health concern even with vaccines and antiviral medications available. Flu strains change from season to season, and some can become resistant to existing treatments.

“We need a bigger arsenal of antiviral drugs,” King said. “There’s a need to develop new antiviral therapies, learn more about how our immune system responds to the virus so that we can develop those new therapies in the future. That’s really the heart of what this research hopes to accomplish.”

King and his students are studying how the body can fight the flu without triggering an immune response so strong that inflammation causes additional harm.

Their work focuses on the renin-angiotensin-aldosterone system, or RAAS. Although it is best known for helping regulate blood pressure, the system also influences inflammation and immune function.

King said the project was inspired in part by a study in the United Kingdom that found people taking high blood pressure medications had a lower incidence of influenza infection.

King and former 91���� doctoral student Brandy Soos followed up on that connection using ramipril, a commonly prescribed blood pressure medication, in the lab’s zebrafish model. In earlier experiments, 90% of influenza-infected zebrafish larvae treated with ramipril survived, compared with 52% in the control group.

The new research will try to understand why.

King believes neutrophils may be an important part of the answer. These cells are among the immune cells recruited to fight influenza. They can help respond to infection, but they can also contribute to harmful inflammation.

To study those cells, the team uses zebrafish. Young zebrafish are transparent, allowing researchers to use fluorescent markers and specialized microscopes to watch immune cells move through a living organism in real time.

Over the four-year project, the team will test how different parts of RAAS change the immune response and its ability to fight the flu.

Students at the center of the research

Student research is a central component of the R16 award. The NIH program supports scientific research while providing substantial hands-on experiences for undergraduate and graduate students.

The R16 award supports 91����’s learner-centered R1 model by placing undergraduate and graduate students directly into federally funded research alongside faculty.

The grant builds upon research funded by the NIH COBRE grant that supports innovative research of several 91���� faculty, an expanded zebrafish facility and new confocal microscope.

In King’s lab, that involvement goes far beyond observing.

“They essentially are doing everything,” King said.

Students work with zebrafish, collect fertilized embryos, prepare fish for experiments and use precise microinjections to introduce influenza virus. They also learn laboratory techniques and use specialized microscopes to track fluorescently marked immune cells in real time.

Graduate student Ben Curtis knows that progression firsthand. He earned a bachelor’s degree in biochemistry from 91���� and worked in King’s lab as an undergraduate before continuing at the university as a doctoral student in molecular and biomedical sciences.

Curtis is helping refine the lab’s influenza model and the methods researchers use to watch the immune response as it happens.

“It definitely gives us an advantage because a lot of the techniques we use cannot be easily done in other animal models,” Curtis said. “We get these very unique insights, and I just love that I can do that.”

Undergraduate researcher Fiona Johnson, a biochemistry major entering her junior year, is studying how immune cells move when certain genes are turned off.

She is testing the role of individual genes using CRISPR, a gene-editing tool, to make those changes in zebrafish and observe how they affect the immune response.

“The fish are really small, and they’re able to be imaged really easily,” said Johnson, also a student in 91����’s Honors College.

Building research experience early

Johnson said her interest in research took off during her first year at 91���� through a phage genomics course that gave students hands-on experience studying viruses that infect bacteria.

The course is part of the Honors College’s Maine IDeA Network of Biomedical Research Excellence (INBRE) program, an NIH-funded initiative that provides undergraduate students with hands-on biomedical research experiences.

“I knew I really wanted to dive into research and use what I’ve been learning in my classes,” Johnson said. She recalled thinking, “I’m in heaven right now. This is exactly what I want to do.”

Shanahan is studying another part of the project: viral burden, or simply how much influenza virus remains in an infected zebrafish.

Her work addresses a question raised by earlier research in the lab. If changing part of the immune response helps a zebrafish survive, researchers also need to know whether the animal is successfully controlling the virus.

“If a zebrafish survives even though it has a higher level of infection, is it because the immune system just didn’t overreact to it?” Shanahan said.

Curtis described the broader goal as giving the immune system “a gentle nudge in the right direction” — helping it respond to the virus without causing excessive inflammation.

The work gives students responsibility for their own research. Curtis said undergraduates conduct experiments, collect data and pursue individual projects that contribute to the lab’s larger research questions.

Johnson is beginning her honors thesis research, while Shanahan said the opportunity to participate in research early in college was one reason she chose 91����.

“At a lot of other colleges, especially in your earlier undergraduate years, you don’t really get the opportunity to do a lot of research,” Shanahan said. “It usually goes to older students.”

King said staying involved in a lab over a longer period allows students to move beyond learning individual procedures and begin developing as scientists.

“Here students conduct research over a longer duration and really master things which distinguishes 91���� from a lot of other schools,” King said.

The research is also teaching Curtis that scientific progress rarely produces tidy endings.

“Once you discover one thing or once you figure out something, that often leads to five new questions,” Curtis said.

Contact: David Nordman, david.nordman@maine.edu.