The Rocahepevirus ratti strain is called “rat HEV” because rats are the primary reservoir of the virus. Since the first human case was reported in a person with a suppressed immune system in Hong Kong in 2018, at least 20 total human cases have been reported — including in people with normal immune function.

People infected with rat HEV did not report exposure to rats, leaving the cause of infection undefined. The suspected cause during other human HEV infections, in many cases, is consumption of raw pork — making it a potential route for rat HEV as well.

Researchers at The Ohio State University found that a strain of rat HEV isolated from humans could infect pigs and was transmitted among co-housed animals in farm-like conditions. Rats are common pests in swine barns — suggesting that the pork production industry may be a setting in which rat HEV could make its way to humans.

“We always want to know which viruses might be up and coming, so we need to know the genetics behind this virus in the unlikely event something happens in the United States that would enable rat HEV to expand,” said senior author Scott Kenney, an associate professor of veterinary preventive medicine at Ohio State based in the Center for Food Animal Health at the College of Food, Agricultural, and Environmental Sciences’ Wooster campus.

The study was published recently in PNAS Nexus.

Hepatitis E is the leading cause of the acute viral liver infection in humans worldwide, mostly in developing regions where sanitation is poor. The virus is also endemic in pigs in the United States — though it is present mostly in liver rather than muscle, and is killed when the meat is cooked.

Past studies testing the cross-species infectiousness of rat HEV showed the strain used in experiments did not infect non-human primates.

“It dropped off the radar for six or seven years because it was thought not to be a human pathogen. And now it’s infecting humans, so we need to figure out why,” Kenney said.

One strain linked to human disease is known as LCK-3110. First author Kush Yadav, who completed this work as a PhD student in the Center for Food Animal Health, used the viral genomic sequence to construct an infectious clone of LCK-3110.

The team first showed the cloned virus could replicate in multiple types of human and mammal cell cultures and in pigs. Researchers then injected pigs with an infectious solution containing the LCK-3110 strain or another HEV strain present in pigs in the U.S., as well as saline as a control condition.

Viral particles in the blood and feces were detected one week later in both groups receiving HEV strains, but levels were higher in pigs infected with rat HEV. Two weeks later, co-housed pigs that received no inoculations also began to shed rat HEV virus in their feces — an indication the virus had spread through the fecal-oral route.

Though infected pigs’ organs and bodily fluids were also positive for viral RNA, the animals did not show signs of feeling sick. Previous research suggests rats don’t have clinical symptoms, either.

Even so, the rat HEV virus was detected in cerebrospinal fluid of infected pigs — a finding that aligns with growing concern that various strains of HEV that infect humans can harm the brain. One human death linked to rat HEV was caused by meningoencephalitis.

“HEV is gaining importance for neurological disorders, and a lot of the research now points toward how neuropathology is caused by the hepatitis E virus,” Yadav said. “And even though we have a small number of known human cases, a high percentage of them are immunosuppressed. That means transplant recipients in the United States could be at risk of infection by general HEV as well as rat HEV.

“Research could now focus on whether pork liver products contain rat HEV and explore food safety procedures to block the disease.”

Yadav is now a postdoctoral researcher in the Virginia-Maryland College of Veterinary Medicine at Virginia Tech. Co-authors of the study, all from Ohio State, were Patricia Boley, Carolyn Lee, Saroj Khatiwada, Kwonil Jung, Thamonpan Laocharoensuk, Jake Hofstetter, Ronna Wood and Juliette Hanson.