On Man’s Best Frenemy

Wug, it’s been awhile. Lots to write about, but I’ve been a laggard.

To the topic at hand. We’ve previously discussed how zoonoses, viruses that spread from animals to man, can be a real biodefense threat (or at least have the appearance of being a biodefense threat, dpending on whether they appear to be natural or man-made). Being a biochemist / evolutionary engineer, I’m not as informed about the possibilities for zoonoses as many others. With that, I recently enjoyed a visit to campus by Colin Parrish, one of the great virologists of our time. I’ve previously learned a great deal from Colin, and this time was no exception.

While the rest of the world runs around and worries about H5N1, the bird flu, Colin thinks there is a threat much closer at hand. He and co-authors such as Eddie Holmes at Penn State authored a paper on “Microevolution of Canine Influenza Virus in Shelters and Its Molecular Epidemiology in the United States” (J. Virol, 84:12636). As you might have guessed, this paper focuses on our pals, the dogs, and the influenza they carry. It’s a particular serotype known as H3N8, and its transmission to dogs is relatively recent. Indeed, it has been shown that “… it was initially recognized in greyhounds in a Florida training facility in 2004 and was then spread around the United States by infected greyhounds in 2004 and 2005 ….” (although it may have been circulating in dogs as early as 1999; at least according to Anderson et al. in the most recent edition of Vet J., hitting your newstand December 16 … or not). Since then it has begun to spread much more widely, and can now be found in dog shelters in the Northeastern United States. If this was a Sherlock Holmes novel, it would be called “The Strange Case of the Parimutuel Betting Disease.”

Why should we be worried about dog flu? Well, we should be worried about the flu in general, but the scary influenza epidemics are the ones where we have very little extant protection, where the viruses have mutated and recombined in an animal host, or more than one animal host, with birds and swine being pervasive reservoirs and providing opportunities for many contacts with man. As the virus changes in one or both species, and as those species come in contact with man, there is always the opportunity that a new variant, an animal experiment from the flu virus’ point of view, will also be transmissible to humans. This has of course happened several times with the H5N1 bird flu, but the second part of the scary equation, the ability to jump not only from animals but between humans has not happened … yet.

It’s hard to predict what changes may be necessary to yield human-ready variants of influenza. It’s just clear that mutations are needed, otherwise we’d already be infected. It’s like the virus is spinning a combination lock with its mutations, searching for the right set of mutations that will allow it to cross over and spread like wildfire in the human population. This is what disturbs me, that spinning of the lock. It happens when a strain is not yet well-accommodated in a given species, when it is first learning how to effectively infect its host.

In this regard, the dog flu didn’t just leap out of nowhere, it “resulted from the transfer of an H3N8 equine influenza virus,” and contains several new mutations that were clearly necessary for or occurred as a result of the crossover to dogs, including 8 amino acid changes in the hemagglutinin protein, the protein that helps influenza interact with cells, whether they be horse, dog, or human. Interestingly, these changes do not seem to have accumulated during the virus’ short tenure in dogs; they may have been present at the time of transmission. That’s comforting; the virus doesn’t seem to be spinning the lock the last few years.

Still, the virus is going to keep on coming. There was a second, independent transfer to dogs in 2007, in Korea. This time it was the H3N2 variant (Gibbs and Anderson, Animal Health Research Reviews, 1:43, 2010). And this time it was out of birds, rather than horses.

The 4-1-1 (as the kids say) can be summarized by an abstract from Vet Clin North Am Small Anim Pract (39:251, 2009) (I have no idea what this stands for; oftentimes even scientists are limited as to what journals are available electronically; them budget cuts, they do eat up our libraries something fierce), by one E. Beeler: “Influenza has long been absent from the list of infectious diseases considered as possibilities in dogs and cats. With the discovery that avian influenza H5N1 can infect cats and dogs, and the appearance of canine influenza H3N8, small animal veterinarians have an important role to pay in detection of influenza virus strains that may become zoonotic.” I couldn’t agree more. I also think that the same wonderful vet that we take our dogs to is utterly unlikely to be cognizant of his role in taking down one of the Horsemen of the Apocalypse (I could be wrong; I’ll ask the next time we need heartworm pills).

So, to summarize: virus jumping into cats and dogs circa 2000, mutations abound, many opportunities for companion animals to get back at you for not giving them that extra treat.

But, well, why? I mean, sure, it may be that the virus is just now getting around to beating on cats and dogs, but that seems weird. They’ve been our companion animals for quite sometime, and both we and our livestock have been overrun multiple times over the last few millenia by influenza variants. Is there something else going on? Eddie Holmes thinks there is: “… there is some evidence for adaptive evolution. Most notably, an analysis of viral population dynamics provided evidence for a major population bottleneck of EIV H3N8 during the 1980s, which we suggest resulted from changes in herd immunity due to an increase in vaccination coverage.” (Murcia et al., J Virol, 85:5312, 2011).

Yes, that’s right, we may have done it to ourselves, again. Horse flu was perfectly content to just beat on horses, and to achieve some sort of rolling genetic optimum that placed it far away from beating on other animals, such as dogs and cats. But along we come with our fancy schmancy vaccines, and in making horses all better, we give the virus little option … but to find new genotypes. And those new genotypes just happen to be far enough afield that they can search for new victims, like dogs and cats. To round out our best intentions gone astray, as the flu spreads in cats and dogs some kindly multinational company will come up with an awesome vaccine for our companion animals, driving the flu into a new hunt for a likely victim. Someone close. Someone who doesn’t go on walks nearly often enough. Someone who hogs the covers at night.

PS: none of the above should be taken as an indictment of vaccine technology. Rather, the evolutionary consequences of vaccination is and should remain an active area of study, as we continue to attempt to predict viral evolution, thus finally getting ahead of these scourges for good.

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