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Fralin Biomedical Research Institute Doctoral Candidate Awarded NIH Fellowship

A dose of adenovirus hits most people like a common cold – a cough, a fever, maybe a sore throat. But for an unfortunate few, the usually benign bug hacks the heart’s cellular electrical communication system and sometimes proves fatal.

Rachel Padget, a doctoral candidate in the laboratory of James Smyth, an assistant professor with the Fralin Biomedical Research Institute at VTC, seeks to learn how adenovirus turns deadly in those rare cases. Her research could also lead to identifying treatments to reduce sudden cardiac death.

A student in Virginia Tech’s translational biology, medicine, and health graduate program, Padget was awarded $101,687 under the National Institutes of Health’s Ruth L. Kirschstein Predoctoral Individual National Research Service Award program to develop a novel way to study how the virus affects heart function.

“Viruses evolve with us and are basically the best cell biologists we know,” said Smyth, Padget’s mentor and an investigator in the Fralin Biomedical Research Institute’s Center for Heart and Reparative Medicine Research. “Anything we learn from how the virus is manipulating how cells communicate could shed potentially important new information on how to address this challenge.”

Smyth and his team’s earlier research found adenovirus attacks a protein called connexin 43, which forms  communication channels between cells called gap junctions.

“What we learn from the viral regulation of connexin could be applicable to all forms of heart disease and possibly cancer. That may hold potential to inform future development of therapeutics,” Smyth said.

Researchers in the Smyth lab focus on how a particular class of heart diseases, also known as cardiomyopathies, manifest at the subcellular level. In a small number of cases, the mild adenovirus can lead to sudden cardiac death.

Cardiovascular disease is the leading cause of death in the United States, according to the Centers for Disease Control and Prevention. Up to 42 percent of sudden cardiac deaths in young adults are caused by myocarditis – inflammation of the heart muscle – and adenovirus is a leading contributing agent to viral myocarditis, the European Heart Journal has reported.

Researchers are addressing the problem by developing a first-of-its-kind mouse model, bearing numerous similarities to human hearts, to observe what happens when hearts are infected.

“Rachel used a strain of mouse adenovirus that we found actually goes to the heart,” said Smyth, who is also an assistant professor of biological sciences in the Virginia Tech College of Science and of basic science education in the Virginia Tech Carilion School of Medicine. “The grant is to develop that model further to facilitate understanding how this viral infection can disrupt the electrical rhythm of the heart.”

That onset of a heart arrhythmia can sometimes cause the heart to stop.

“In times of stress, your cells are able to change how they make proteins, and they’re able to prioritize making survival proteins or immune response proteins,” Padget said.

Adenovirus stops cells from initiating that response.

These effects from the virus are nearly impossible to detect during its acute phase. If the infection reaches the chronic stage, the effects are more apparent – an enlarged heart or visible lesions. But there are no diagnostic tools for the acute phase except a highly invasive biopsy to collect a small amount of heart tissue.

Another of Smyth’s graduate students, Patrick Calhoun, won an American Heart Association grant in 2018 to study adenovirus effects on human heart cells in culture.

Now, with the mouse model, researchers can better study the electrical system that keeps a heart beating and learn more about the effects a virus can have on that system in the heart.

“What Rachel is really looking at is the active infection of the heart before an immune response,” Smyth said, “and so, what the virus is doing to the heart, and she’s found that during this very early stage, the heart can be dangerously susceptible to arrhythmias.”

Padget, who joined Smith’s lab in 2017, may have been pre-disposed with a calling to do heart research. She was born with a heart defect. It healed on its own, but was a subject of conversation with her family as she grew up in Odessa, Missouri.

She earned a bachelor’s degree in biochemistry from the University of Central Missouri and studied vascular development in the context of heart defects for her master’s degree at Missouri State University.

Padget’s work could provide fundamental understanding of processes that could contribute to future therapies to head off sudden cardiac death, including by addressing that viral hijacking of cells’ immune response.

Padget is the third graduate student in Smyth’s lab to land a significant research grant, joining Calhoun and Carissa James, who also won a Kirschstein fellowship in 2018.

“These are national competitions. The grants acknowledge the trainee, the training environment, and the mentor,” Smyth said. “It’s a huge thing for Fralin Biomedical Research Institute that we’re being so successful in getting these awards.”

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