Medical student's research informs understanding of cellular communication during viral heart infections
Heart infections caused by viruses can be serious, particularly for young adults and children.
“We believe myocarditis – inflammation of the heart tissue often caused by viruses – is responsible for about 42 percent of sudden death in people 35 and younger,” said James Smyth, assistant professor at the Virginia Tech Carilion Research Institute in the Center for Heart and Regenerative Medicine Research. “It has become increasingly prevalent in children and infants and connected to Sudden Infant Death Syndrome (SIDS).”
Currently, there is not much research on the mechanisms of viral myocarditis such as how viruses may target cardiac cell gap junctions, which allow cells to communicate. That was the starting point for the work of now fourth-year Virginia Tech Carilion School of Medicine student Vu Phan when he joined Smyth’s lab three years ago.
“For Vu, I wanted to start the virus work in the lab and ask, what is the fate of these gap junction channels in the context of viral infection?” Smyth said.
They looked at adenovirus, which typically causes mild respiratory illness. But, some strains can attack cardiovascular tissue.
“When the virus infects the lungs, you get sick and get a cough. The cells stop communicating with each other and they make viruses. But in the heart, if a virus changes how those cells are communicating with each other, that can lead to an arrhythmia,” Smyth said. “Unlike skeletal muscle cells, cardiac cells work independently, but they have to talk to each other. If they stop talking, then you have a short circuit and that can kill you.”
Phan was tasked with seeing how the adenovirus targets the cells’ gap junctions, making it easier for the virus to spread. “Gap junctions are really important because they link cells and allow for the passage of small molecules in between them,” Phan said.
In particular, Phan worked to see if the virus targeted the protein connexin, which composes gap junctions.
“Connexin has the ability to build gap junctions and the way they link cells, but they can have a variety of functions in terms of cell signaling. When you look specifically at the heart, it also regulates the conduction of an electrical signal through the heart,” Phan said. “It's been shown too that when you disrupt that connexin, there are pathological changes. In the heart, that could lead to heart disease or arrhythmias.”
Through Phan’s work with others in the lab, under the mentorship of Smyth, they discovered the virus did indeed target the connexin protein. Vu was able to mutate the expression of connexin. In cells without connexin, the virus thrived. When the virus was exposed to cells where connexin could not be removed, the infection slowed.
Next, they wanted to know how connexin slowed the virus down.
“Surprisingly, Vu found it was actually the intracellular communication factor that was the key to the cell stopping the virus. This has laid the work for now half of my lab,” Smyth said. “Our hope is what we learn from this virus we can apply to all forms of heart disease where there are changes in connexin by identifying the substrates of these key regulator hubs. The virus is limited in how much information it can package. It is under extreme evolutionary pressure. It only has the essential information in its genome. It doesn't have any junk DNA. Whatever it does, it does well. That's why we are interested to see how it is regulating connexin so we can see if we can target these pathways globally. Vu helped us get this work off the ground in the lab.”
In 2016, Phan delivered an oral presentation about the project at the American Society for Virology’s annual meeting, with more than 1,300 scientists from the U.S. and abroad.
“That was one of the cooler aspects of being able to work in Jamie's lab, quite honestly," Phan said. "The fact that he's giving me this level of responsibility not only to carry out the project but also to present it on an international stage in front of other really experienced researchers in the field was exciting and an honor.”
Most recently, Phan was able to share about his research experience while on the interview trail for residency programs, which will be his next step when he graduates from VTCSOM in May. While his research may seem unrelated to his pursuit of psychiatry programs for his specialty, he said it still helped him stand apart from other candidates.
“There was value in being able to show my ability to talk clearly through cutting edge research, to be able to explain it clearly, to boil it down into its fundamental concepts, and talk about the impact of it,” Phan said. “When residency program directors saw that, it showed something of myself in terms of my ability to talk to people and teach, as well as my ability to conduct research and think through research as well.”
Having received a Letter of Distinction for his project, Phan will be one of eight students from the class of 2018 giving oral presentations as part of the VTCSOM Medical Student Research Symposium. In addition, the rest of the class will be giving poster presentations at the event, which will be held during the afternoon of March 23. Read more.