As an Associate Editor for Emerging Infectious Diseases and as a frequent peer reviewer for other journals, I see lots of paper that report finding a “new” virus. These can be a challenge to interpret, because advances in technology now let us find things we’ve never been able to find before. The problem is, we can find things a lot more easily and quickly than we can understand them, and it’s easy to jump to questionable conclusions.

Let’s say we look at individuals with a certain disease and we find a specific virus in many of them that we haven’t seen before. That’s interesting, but in terms of proving that virus could be a cause of disease, it’s only step one of many.

Maybe we then test a few other animals with the same disease and find the same virus.  Convincing, right?

• Not necessarily.  We live in a microbial world, and lots of microbes live on or in us all the time. We have a “commensal microbiota” of bacteria, viruses, fungi and parasites with which we co-exist. Some help us.  Some can hurt us at times. Mostly we live blissfully unaware of their presence.

So, finding X virus in people or animals with Y disease could mean that it’s a cause, or that it’s a normal inhabitant of the microbiota that we finally just noticed. Or, it could be something that’s relevant but only when some other microbe is present as well.

I see lots of papers that stop at this step. They find a virus (or often just genetic bits of a virus, not the whole virus or even evidence of a live virus) and link it with a disease. Sometimes they’re right (or lucky). Sometimes they’re wrong, and that sends people down some unnecessary paths.

The next step in the process is looking at similar but healthy individuals to see if the implicated microbe is found in them too, or only in the sick individuals. If so, that’s still not a guarantee it’s the cause of disease, but it provides much more solid evidence.

That was a long preamble to the actual topic of this post:

“Staggering disease” is a unique and interesting neurological disease found in cats in some parts of Europe. Clinically, it usually causes hind limb ataxia resulting in a staggering gait. Various other neurological signs can be present, but hind limb ataxia is the most consistent, obviously giving rise to the disease’s name. First described in the 1970s, the cause has been elusive, but a virus has long been suspected. Borna disease virus 1 (BoDV-1) was previously a leading candidate, but has fallen out of favour lately.

A recent preprint (Matiasek et al. 2022) may have answered the question of what causes staggering disease in cats. They started off looking for Borna disease virus in 29 affected cats from Sweden, Austria and Germany. They went 0/29, using both PCR and immunohistochemistry. That might put to rest suspicions that Borna disease virus is involved in the disease.

Then, they used a metagenomic approach to identify genetic material from any virus that might be present in the cats. Unlike PCR, where you must have a target, metagenomics lets you find snippets of virus genetic material that you can then try to stitch together into larger fragments, and compare them with known viral genomes to identify what’s there.

Using this approach, they found sequences that matched Rustrela virus (RusV) in 14/15 samples tested. They then developed a new PCR test for RusV and got positive results from 15/15 cats from Sweden, 8/9 from Austria and 3/5 from Germany. They followed that up with some other tests of brain tissue (in situ hybridization, immunohistochemistry) to confirm the presence of the virus. Overall, 28/29 cats tested positive for RusV with at least one of the tests. Importantly, samples from 21 cats without encephalitis and 8 cats with encephalitis of other causes were all negative.

Rustrela virus is a close relative of rubella virus (which causes rubella in people). That doesn’t mean there’s any link with people or rubella virus, but it helps us understand more about the virus. Rustrela virus has also previously been found in the brains of a few different mammals with neurological disease in a zoo in northern Germany.

Even if Rustrela virus is the cause of staggering disease, lots of questions remain. A big one is waht is the virus reservoir? Does it circulate only in cats, or spillover from other species (e.g. wildlife)? That will take a lot more work to figure out, but they started looking into it by testing brains of 116 rodents from Sweden that were caught between 1995-2019 for other studies. Using PCR, they got positive results from 8/106 (7.5%) wood mice. None of the infected mice had changes in their brain, which fits with a reservoir species that can carry (and spread) the virus, potentially for a long time, because it doesn’t cause disease in the host. If the virus lives in the brain of the mice, cats could be exposed through hunting, but a lot more work needs to be done to look at virus shedding and transmission routes.

I assume we’ll be hearing a lot more about this virus in coming years as more work gets done. It’s not a slam-dunk, but this seems pretty convincing, and definitely enough to launch more studies since lots of important questions remain.