Norovirus is not a subtle type of viral infection. Instead, it can cause days of nausea and vomiting.

Norovirus is also highly contagious, spreading from infected people by either direct contact or through contamination of food or surfaces. It is the leading cause of food-borne illness in the United States, sickening about 20 million people per year, according to the Centers for Disease Control and Prevention.

And it’s just as aggressive at a cellular level. As it reproduces inside cells, it punches holes in mitochondria to kill and burst cells open, researchers at UT Southwestern have found.

The researchers discovered that the viral protein responsible, called NTPase NS3, resembles one naturally produced by host cells. The host protein binds to the outer cell membrane, but NS3 instead binds to mitochondrial membranes – a change that’s deadly to the host cells.

Researchers from the Reese lab who participated in the study focused on a viral protein called NS3.

By opening holes in the mitochondria, NS3 destroys the cell’s energy source and causes highly reactive molecules to spill into the cell and cause havoc.

“In the evolutionary arms race between viruses and their hosts, viruses steal host proteins and repurpose them for viral replication,” said Tiffany Reese, Ph.D., Assistant Professor of Immunology and Microbiology. “Our work suggests a new putative target for antiviral therapies.”

Dr. Reese’s team joined with Dustin Hancks, Ph.D., Assistant Professor of Immunology for the study, which was published March 29 in Nature.

Dustin Hancks, Ph.D.

Previously, NS3 was known to replicate viral genetic material, but its role in cell death was undetermined. The UTSW team tackled the problem pinpointing its purpose using mouse models, cell cultures, genetic engineering, protein modeling, and other methods. They also compared NS3’s actions to other types of cell death: apoptosis, necroptosis, and pyroptosis, which are well-regulated, normal cell processes.

NS3 bypasses these known biochemical pathways, the team found.

Understanding how noroviruses rupture cells could lead to new therapies against the virus and opens a new way for killing cancer cells. Using customized viruses to destroy cancer cells is a new field, with only a few such viruses approved or used in clinical trials currently. These “oncolytic viruses” work in a variety of ways, and if NS3 could be incorporated into them, it might be possible to cause cancer cells to burst.

“Egress [from the cell] is probably the most poorly understood viral process,” Dr. Reese said.

By studying NS3, researchers might also learn more about the host “death protein” that it mimics. This protein, called MLKL, is involved in necrosis and in some inflammatory disorders. “We want to use norovirus NS3 to identify new host proteins involved in regulated cell death,” Dr. Reese said.