Mentorship guides a PhD student from puzzling result to RSV discovery

Becoming a scientist means learning how to investigate the unknown, which is unpredictable by its very nature. Experiments rarely move in a straight line, and some of the most important discoveries emerge when results do not fit the original hypothesis. Having high-quality mentorship can be the difference between successfully navigating a project’s unexpected twists and turns to reveal new knowledge about the world or getting stuck within the maze of the undiscovered.

That was the case for Kendall Whitt, PhD, who recently obtained her doctoral degree from the St. Jude Graduate School of Biomedical Sciences. In the lab of her mentor, Stacey Schultz-Cherry, PhD, Department of Host-Microbe Interactions, Whitt studied respiratory syncytial virus (RSV), the most common cause of pediatric hospitalization in the world. She uncovered results that ran against expectations, but together with Schultz-Cherry, Whitt turned what was at first perplexing into helpful new insights about RSV.

“Stacey was fantastic from the start,” Whitt said. “She trusted me to start studying RSV in her lab, which normally focuses on influenza, and connected me to her colleagues when the virus didn’t behave as we had hypothesized.”

Schultz-Cherry’s lab helped establish an entire field of research examining how metabolic dysfunction, induced by a high-calorie diet, worsens influenza virus infections. Originally, Whitt planned to test the phenomenon of co-infection, where two viruses infect the same person at the same time, in mouse models of metabolic dysfunction. However, early experiments repeatedly suggested something unexpected: RSV caused less severe disease in those models than in controls.

Following this interesting but confusing finding, Whitt decided to characterize RSV infection alone in these models without co-infection. The results confirmed that models on a high-calorie diet had less severe RSV disease than animals kept on a lean diet. The findings were recently published in mBio.

Characterizing a counterintuitive result

“Normally, the infectious disease field thinks of metabolic dysfunction as a universal cause of more severe disease,” Schultz-Cherry said. “Kendall’s work showed that not all viruses act the same, and that we need to think about co-morbidities, such as obesity, in the context of a specific viral infection’s pathology.”

When Whitt examined the immune responses of these models, those fed a high-calorie diet that were then infected with RSV had a significantly reduced, but still protective, immune reaction to the virus. They also had fewer signs of damage or “pathology,” such as injured tissues, suggesting a reason for the discrepancy.

“Damage from RSV infection is primarily from the immune response to the virus, not from the virus itself, unlike influenza,” Whitt said. “So, our work suggests that an animal with metabolic dysfunction has a weaker antiviral immune response, which in the case of flu allows the virus to do more direct harm, but in the case of RSV, that same immune dampening may also lessen immune-mediated disease pathology.”

That unconventional conclusion required strong mentorship and guidance to reach, especially for a PhD student on an unconventional path spanning technology, medicine and research.

Supporting an unconventional path

Unlike most graduate students, before coming to St. Jude, Whitt had worked in biotechnology and then started medical school. However, during her first two years in medical school, she also participated in laboratory research with Schultz-Cherry and discovered a passion for it. “That experience confirmed that I wanted research to remain part of my life and that I wanted to train as a physician-scientist,” Whitt said.

While committed to finishing her medical education, she decided to take a detour, applying to the St. Jude Graduate School at Schultz-Cherry’s insistence, with an explicit plan to return to medical school after completing her PhD. That trajectory paired well with the school’s unique ability to provide support when her project took its unanticipated turn.

“That flexibility is one of the strengths of the Graduate School,” Schultz-Cherry said. “In a traditional university setting, Kendall probably would not have had the freedom to pivot so drastically, but the Graduate School provides every student with dedicated support to pursue where their project takes them, without pre-existing requirements, and I had the freedom to encourage her to do so.”

When Whitt first found that RSV acted differently from influenza, the results were perplexing. Schultz-Cherry did what experienced mentors do: She encouraged Whitt to repeat the experiments in multiple ways to see if the same results would occur. Once it was clear that the counterintuitive results were replicable, Schultz-Cherry turned to her network of colleagues at St. Jude — those with extensive RSV experience — to provide additional guidance to both her and Whitt.

“As an advisor, it is devastating because you want to help such a promising student and project, but I lacked those practical insights into working with RSV that I have for flu research,” Schultz-Cherry said. “But what I did have was a network and community I’ve built over the course of my career, and the flexibility let her explore this project with their guidance.”

It takes a village to mentor

Schultz-Cherry introduced Whitt to other scientists, including the RSV experts Asunción Mejías, MD, PhD, Department of Infectious Diseases; Octavio Ramilo, MD, Department of Infectious Diseases chair; and Steven Varga, PhD, the Graduate School dean and Department of Infectious Diseases member, who were recruited to St. Jude while Whitt was working on her thesis project. With their input, Whitt was able to navigate the technical challenges of RSV research and better detail the immune response to its infection. Comparing RSV infection between models with and without metabolic dysfunction, she found that two types of white blood cells, macrophages and CD4 T cells, and a group of immune signaling proteins called cytokines, were different between the groups, but in a surprising pattern.

“Most research into RSV severity has focused on the adaptive immune response, which comes seven days or later after infection,” Whitt said. “Our results show that the cells and signals of the innate immune response, which happens early, are dampened by metabolic dysfunction, which suggests innate immunity is helping determine how much pathology develops, indicating the field may need to widen its focus to include studying innate systems to understand RSV’s pathology better.”

These findings add nuance to the research. There are many well-documented vulnerabilities to infectious diseases in those with metabolic dysfunction, so the study does not promote high-calorie diets as a protective measure. Instead, Schultz-Cherry and Whitt worked together with the community at St. Jude to articulate what the counterintuitive study means for infectious diseases.

“One thing that makes St. Jude special is the ability to think beyond the standard ‘healthy host’ model,” Schultz-Cherry explained. “We can ask what infectious disease looks like in immunocompromised or otherwise vulnerable populations. This helps us understand not just disease, but also how care may need to differ. In that context, these results show that we need to consider how RSV and other infections change when people have comorbidities, such as metabolic dysfunction, and how we can use that knowledge to help them.”

Saying farewell to a future physician-scientist, for now

Whitt has now earned her PhD and, as planned, is returning to medical school. “Stacey’s support, and the help of everyone at St. Jude, helped me navigate this project, especially as it matured and deviated from all of our expectations,” Whitt said. “One day, I hope to have my own lab and specialize in infectious disease care clinically, to return the favor and help us better understand these viruses on a fundamental level while also seeing how we can directly improve patients’ lives.”