Cause of Mystery Mouse Disease Discovered
Cause of Mystery Mouse Disease Discovered

Cause of Mystery Mouse Disease Discovered

Lab mice suffering from inexplicable renal failure turn out to be infected with a hitherto unknown virus.

Sep 13, 2018
Ruth Williams

ABOVE: MKPV infected mouse kidney tubules (red) and resultant fibrosis (white).
BEN ROEDIGER, CENTENARY INSTITUTE

For decades, an unexplained kidney disease has been striking certain middle-aged laboratory mice. Researchers have finally discovered that it is caused by infection with a novel parvovirus. The newly discovered virus, described in Cell today (September 13), is distinct from previously identified mouse parvoviruses, instead sharing sequence similarities with viruses found in a diverse set of animals including bats, rats, and pigs.

“Even in an intensely studied animal like the laboratory mouse there are infections that we haven’t identified, that are widespread, and that can cause significant clinical manifestations,” says Colin Parrish of Cornell University College of Veterinary Medicine in Ithaca, New York, who was not involved in the research. “We’re still discovering these [viruses] and we really don’t know how many more there are to be found. There’s no reason to think this is the last.”

Over the past 40 years there have been anecdotal reports of laboratory mice succumbing to an unexplained renal failure in middle to older age. The disease most often afflicts animals engineered to be immunocompromised, and the general consensus has been that “this is just a problem that shows up in these strains,” says Ben Roediger of the University of Sydney’s Centenary Institute in Australia who led the new research.

In 2010, when mice at the Centenary Institute’s animal facility started dying prematurely from kidney problems, Roediger suspected an infection was to blame.

For one thing, the illness wasn’t specific to mice of one particular genetic background—many immunocompromised strains got ill. Furthermore, only certain animal lines of a particular strain were affected, suggesting the disease wasn’t an inherent strain-associated problem. And, when the team examined the pathology of the disease, the kidney cells showed a classical hallmark of viral infection—clumps of proteins called inclusion bodies in the nuclei.

Perhaps one of the most telling results, however, was that housing healthy mice with diseased ones resulted in the healthy animals becoming sick.

More than a decade ago, researchers in the US had also suspected this strange kidney disease might be caused by a viral infection, but attempts to identify virus particles by electron microscopy had failed, as did efforts to amplify known viruses from diseased kidneys.

“We couldn’t see the virus with electron microscopy either,” says Roediger, but the development of next-generation sequencing technology meant the team had another tool at its disposal.

The group extracted and sequenced RNA from the kidneys of a very sick mouse, filtered the data to remove known murine sequences, and focused on the most abundant remaining unassigned sequences. Two sequences with matches to parvovirus proteins “popped straight out,” says Roediger. He knew with “absolute certainty, that this is it,” he recalls, “It all just clicked into place.”

“It’s an example of fortune favoring the prepared mind,” says Parrish.

The team went on to isolate the whole 4,442-nucleotide genome of the virus the researchers call mouse kidney parvovirus (MKPV). They showed that it was most closely related to parvovirus sequences found in fruit bats from Ghana, vampire bats from Brazil, as well as in wild rats and pigs.

From the sequence, the team designed primers for amplifying the virus and set about testing their diseased and nondiseased animals, confirming the presence and absence of the virus, respectively. The investigators also analyzed samples from mice suspected of having the same disease from other laboratories in the US and Australia. Sure enough, the animals tested positive.

“How widespread the virus is, is still to be determined,” says Eric Delwart of the University of California, San Francisco, an expert in virus discovery and evolution who was not part of the research team. But, it will be important to find out, he adds. “If you have an experiment where half of your mice are infected and the other half are not, that can really mess up your data.”

Indeed, MKPV, which causes severe illness in immunocompromised mice, but can exhibit mild or subclinical symptoms in wildtype strains, “could be causing all manner of variation in experimental outcomes,” says Roediger, particularly for studies examining mice into middle and old age. It’s therefore important that researchers, and especially mouse vendors, screen for and eliminate the virus from their animals, he says.

On the flip side, MKPV may actually be of use in the field of kidney research, says Roediger. It could be engineered as a vector to target kidney cells, or used as-is to model chronic kidney disease such as that caused by virus reactivation during kidney transplantation, he says. “There’s always a silver lining.”

B. Roediger et al., “An atypical parvovirus drives chronic tubulointerstitial nephropathy and kidney fibrosis,” Cell, doi: 10.1016/j.cell.2018.08.013, 2018.