Aiming at a New Target to Stop a Widespread Common Virus

Yuecheng Xi, PhD, grew up wanting to be a pharmacist. But five years ago, after completing undergraduate degrees in pharmacology and toxicology, her father died from a herpesvirus he contracted after a kidney transplant. The experience changed Dr. Xi’s life.

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“That is what started my interest in this virus,” said Dr. Xi, whose postdoctoral work at the University of Arizona Health Sciences focuses on the human herpesvirus type 5, more commonly known as cytomegalovirus (CMV), a pathogen that can be deadly in immunocompromised people, including transplant patients.

“I was looking for a lab that focused on this work and I found Dr. John Purdy's lab, which studies how the virus manipulates the host cells’ metabolism to replicate,” Xi added.

Since 2017, Dr. Xi has worked alongside John Purdy, PhD, assistant professor of immunobiology at the UArizona College of Medicine – Tucson, to understand how this common virus replicates. According to the Centers for Disease Control and Prevention, more than 50% of U.S. adults over 40 have CMV. It also is the leading cause of viral birth defects such as hearing loss, blindness, developmental disabilities and microcephaly (small head).

Creating defenses against disease

Dr. Purdy’s lab contributes to a larger UArizona Health Sciences strategic initiative called Personalized Defense, which addresses issues related to immunity, infection, inflammation and aging. Researchers in Dr. Purdy’s lab are zeroing in on complex metabolic interactions between viruses and host cells with the goal of better understanding of CMV biology to aid developing new antiviral therapies.

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Viruses replicate by hijacking a host cell and using it to provide energy and building blocks – nucleotides, amino acids and lipids – for new viruses. Lipids perform three key biological functions: they serve as structural components of cell and virus membranes; they store energy; and they act as signaling molecules to facilitate other biological events.

“In normal human biology, cells generate many lipids to keep themselves happy, and the virus has evolved to take advantage of that process,” said Dr. Purdy, who also is a member of the BIO5 Institute and the Cancer Biology Program. “We want to uncover a molecule that will limit the ability of the cell to make the lipids the virus needs to set up a successful infection.”

In the lab, Dr. Xi purifies samples of CMV, adds them to cells, and tracks the process by which host cells make lipids and how the virus behaves during this interaction. She looks closely at the interactions that help viruses thrive.

In the short time Dr. Xi has been a part of Dr. Purdy’s lab, her work has already led to some answers.

Finding solutions, one step at a time

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“We found that CMV infection induces an abundance of newly synthesized lipids that have very long chain fatty acid tails, including some newly synthesized lipids that did not exist in the host cell originally,” Dr. Xi said. “We are trying to figure out the importance of those very long chain fatty acids. We want to understand the mechanism by which the virus manipulates the host lipid environment and the importance of those lipids, biologically, to either the virus or the host.”

Dr. Purdy says Dr. Xi has advanced the research by focusing on the mechanisms that viruses use to make new lipids and the stress response in host cells.

“What she has learned is the virus takes advantage of a stress response to reprogram lipid metabolism,” Dr. Purdy said. “Her work is uncovering what the virus is doing to the host to replicate and how the host cell is regulating lipid synthesis, learning not only about the virus, but about human biology.

“Her work aims to shut down the synthesis of some of these lipids. She aims to trick the cell into turning off certain processes to cut the virus off from what it needs,” he continued, adding that he hopes to expand opportunities for post-doctoral researchers with the support of the UArizona Health Sciences Personalized Defense strategic initiative.

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Dr. Purdy, who has been studying viruses for decades, is laser focused on continuing his work on CMV. In addition to its impact on immunocompromised adults, CMV is the most reported viral infection in newborns, and nearly 1 in 3 children in the U.S. will be infected with CMV by age 5, according to the CDC. When conditions are right, the virus can wreak havoc, causing disability and, sometimes, death.

“A virus can do very interesting things to help support its replication,” Dr. Xi said. “Lipids, overall, are induced upon infection. The most interesting thing is that several lipids with very long chain fatty acid tails did not exist in the host before and only show up upon infection. It seems that viruses need these very long chain fatty acids for some reason. We have some preliminary thoughts, but they are still not fully understood. Exploring the importance of these very long chain fatty acids to viral infection is critical for drug discovery as a potential target in the future.”