The first known case of rat hepatitis jumping to a human patient has reopened a long-standing mystery of how the cryptic viruses spread and bounce between humans and animal reservoirs.

Last Friday, September 28, researchers at the University of Hong Kong revealed that a 56-year-old-man had contracted a strain of hepatitis E previously thought to only infect rats. Hepatitis E viruses, generally, cause liver inflammation in humans that is usually self-limiting but can become severe or even fatal to some, including organ transplant patients and pregnant women.

Researchers spotted the man’s infection back in September of last year, after he had undergone a liver transplant in May. They reported that the man’s infection was treated and cleared by March of this year, after which they verified the presence of the unexpected virus and tried to track down its source.

In the course of their work, the researchers ruled out the possibility that the man was infected from his organ or blood donors. Instead, the researchers noted evidence of a rodent infestation near the man’s home with noticeable collections of droppings by a next-door garbage chute. Testing of at least one rat collected in the neighborhood in recent years had turned up positive for rat hepatitis E, the researchers reported.

Infectious disease expert and microbiologist Yuen Kwok-yung, of the University of Hong Kong, described the case “a wake-up call” in a press conference. He said some of the city’s rats had become larger than cats and urged officials to improve sanitation to avert public health risks from the menacing rodents.

While the suggestion may not be a bad idea, there’s no need to panic, yet, according to hepatitis E expert X.J. Meng of the VA-MD College of Veterinary Medicine at Virginia Tech. “This has never happened before,” Meng noted of the virus jumping from a rat to a human. It’s “unprecedented” he went on to say in an interview with Ars. “Regardless, I do not personally think this [case] is a major public health issue.”

Still, the news does spotlight the lingering mystery around the little-known form of hepatitis.

Enigmatic infections

Meng notes that there have been several attempts by researchers in past years to see if hepatitis E from rats could spread to humans—it has been a piece of the long-standing puzzle surrounding how the virus spreads. Generally, the transmission tests were done by seeing if virus from rats could pass to non-human primates or pigs in labs. So far, all of the attempts have failed. And, Meng explains, we know that rat hepatitis E—like the rest of its ilk—spreads through a fecal-oral route, which works exactly as it sounds. Essentially, for the rat virus to become a major public health crisis there would have to be a situation such as a significant amount of rat feces contaminating a source of drinking water, he speculated.

In the case of the 56-year-old man in Hong Kong, Meng speculates it was just an unlucky twist of fate that he got the “first infected” title. His immune system was likely suppressed following the liver transplant (to help his body accept the new organ), making him much more susceptible. And it seems he just happened to have a high chance of exposure from his environment.

Still, the rare rat case gnaws at the lingering questions of hepatitis E that Meng and other infectious disease trackers have chipped away at for several decades.

Researchers have long documented that human versions of the virus cause outbreaks of acute liver inflammation in developing countries, typically in cases where fecal contamination seeps into water sources. The human viruses cause an estimated 20 million infections a year around the world, leading to tens of thousands of deaths, according to the World Health Organization.

But in the late 1990s, researchers started noticing that surprisingly high numbers of blood donors in the US and other developed countries were showing up with anti-hepatitis E antibodies in their blood (which is typically evidence of a past infection). The researchers couldn’t figure out why or how these donors were being exposed to the viruses, absent international travel.

The findings hinted that people may have somehow come down with subclinical infections that cleared up on their own, Meng said. But if they did have the infection, it’s unlikely we would have been able to figure it out. When doctors are treating liver inflammation or other viral illnesses, they tend to think of the other hepatitis viruses first, A, B, C—but not E, he said. “This disease is grossly under-diagnosed in many countries,” and “we do not have an FDA-approved diagnostic test” for it, he added. If we did, “I’m sure that you’re going to see more cases reported in the clinics.”

The lack of diagnostics is part of a larger problem, Meng notes. “This is a very important public health pathogen, but it’s extremely under-studied. There are very few labs that study this virus.”

Germ jumble

The few researchers on it, however, have figured out that there are at least four types of hepatitis E that infect humans, aka HEVs. They’re HEV genotypes 1, 2, 3, and 4. Researchers have collected genetic evidence that these HEVs can also infect a variety of animals, including pigs, wild boar, deer, rabbits, mongoose, chickens, camels, ferrets, greater bandicoots, Asian musk shrew, mink, moose, and fish. HEV G3 and G4, in particular, have been found to spread directly from pigs and wild boar to humans.

There are other strains (HEV-like strains) that infect rats and ferrets. These are genetically different from the HEVs, Meng points out, and there has been no evidence (except for the new case) that rat hepatitis E can spread from rats to humans. The genetic analysis of the strain infecting the patient in Hong Kong hasn’t been published yet, but researchers reported that it was “highly divergent” from the strains that infect humans.

Yet, in recent years, there have been numerous but controversial reports of rats being able to catch—and potentially spread—the HEVs themselves. This would be a tidy explanation of how humans, particularly ones in urban areas of developed countries, may be exposed to HEVs.

In 2010, researchers reported molecular evidence of HEV infections in wild rats in Hamburg, Germany. In subsequent years, researchers found further evidence of HEV in wild rats in Los Angeles and, more specifically, HEV G3 in wild rats from various places in the US. Still, researchers’ attempts to infect rats in labs with HEV have been hit or miss. And—except for the new case in Hong Kong—no one has caught viruses hopping from rats to humans.

In a 2016 article, Meng noted that we likely don’t know enough about hepatitis E viruses to figure out what's going on. We may only have a glimpse of their genetic diversity in the wild, and we still don’t understand their life cycles or the full range of animals they can infect. “Significant progress in HEV research has been made in the past decade,” Meng concluded, “but many important questions remain.”