Dog days

Did stray dogs spread Covid-19? A controversial connection explained

"It's an interesting story. I think the part about dogs is wrong."

Like many other coronaviruses, SARS-CoV-2, the virus that causes Covid-19, likely made the leap from bats to humans. But scientists believe there was a middleman host, an animal between the bats and ourselves. At first, researchers thought snakes might be to blame (now refuted). Then they thought it might be pangolins.

Now, a scientist proposes a new candidate: Man's best friend.

Stray dogs may be the intermediate hosts for the novel coronavirus, facilitating its jump from animals to humans, according to a new analysis by Xuhua Xia. Xia is a professor in the Department of Biology at The University of Ottawa.

Xia's research poses a genetic explanation for the theory that stray dogs carried SARS-CoV-2 to humans.

Dogs' intestinal tracts create a perfect environment to shape the genome of the coronavirus, allowing it to evolve to infect humans, Xia suggests. The argument boils down to a single dinucleotide in the viruses' genome called CpG dinucleotide. As Xia notes in the paper, SARS-CoV-2 has the "most extreme deficiency" of the molecule amongst all known betacoronaviruses.

That absence signaled to Xia that there could be some evolutionary reason that this dinucleotide was missing from the viral genome.

Previous studies have shown that CpG acts as a landing pad for a protein called ZAP, which, in mammals, targets viruses and chops up their genomes. Interestingly, studies on HIV (a single-stranded RNA virus like SARS-CoV-2) show that when is CpG increases, the virus fails to replicate.

SARS-CoV-2 may have, at some point, dwelt in a host with high ZAP proteins, which in turn, caused the virus to lose CpG dinucleotides as it evolved in that environment. Xia's paper suggests that the canine digestive system, which is rich in ZAP proteins, is an obvious candidate.

The theory is detailed in a paper published Tuesday in the journal Molecular Biology and Evolution.

Bad news for Good Boys? — This is just one study. When Inverse spoke to Xia, he cautioned that scientists need to look for potential coronavirus evolution in many more animal species, not just the usual suspects, like bats.

"It is relevant that in the future surveillance programs should include canine species," Xia tells Inverse.

"If we have sampled all the mammalian tissues and the canine species is the only one that favors the origin of SARS-CoV-2, then we can very well conclude that the canine digestive system is probably key contributor to the evolution of SARS coronavirus."

The theory could have significant implications for the roughly 200 million stray dogs around the world. India alone has an estimated 30 million stray dogs. In China, there have already been instances of dogs being abandoned, killed, or hurled from balconies, after a debunked rumor spread on Chinese social media claiming that they can spread the virus.

Vincent Racaniello is a professor of microbiology and immunology at Columbia University, who was not affiliated with this study, tells Inverse that this paper is built on some compelling virology that may help uncover the source of SARS-Cov-2.

But as for the dog connection, he's skeptical.

"I think the part about dogs is wrong."

"It's an interesting story," he tells Inverse . "I think the part about dogs is wrong."

Though this study suggests stray dogs could have been intermediate hosts for SARS-CoV-2, other scientists urge caution. Christopher PB/Shutterstock

Xia agrees that his results are, at this point, highly preliminary.

"I just wanted to see if there was one tissue where genomes of low CpG are also found," he says.

"Then I found there were these canine coronaviruses that infect canine digestive systems. They have low CpG. That indicates that canine intestine or digestive system favors the evolution and origin of these low CpG genomes."

Racaniello agrees the virus likely traveled via a host with this kind of high-ZAP environment. But to hone in on dogs is premature. That is because ZAP is a defense protein, he says. Resting levels of ZAP aren't useful to look at in this context, because they spike when you're infected with a virus

"I think ZAP-CpG is a really interesting axis here. But the idea that dogs are the intermediate host isn't quite right."

Adolfo Garcia-Sastre, a professor of microbiology at Mt. Sinai's Icahn School of Medicine, says using CpG deficiency to trace the origin of the coronavirus is "interesting."

But to speculate that the virus' genetics selected for low CpG is "a big jump, and extremely unlikely," he tells Inverse.

There is other data to suggest dogs may be off the hook when it comes to spreading the virus that causes Covid-19 to humans.

Dogs aren't good hosts  In a study published in Science last week, scientists tested infecting dogs with SARS-CoV-2 in the lab.

They found that the novel coronavirus struggled to replicate in dogs compared to cats. In our feline friends, the virus was able to flourish in the respiratory system, but not the lungs.

The results suggest that a dog's body is not particularly homey for the coronavirus.

"People have tried infecting dogs with SARS-CoV-2 and they're not efficiently infected so the idea that they're an intermediate host, I don't think, is correct either," Racaniello says.

Xia points out that the Science study leaves some questions unanswered. His work suggests that the dog digestive tract is one potential, ancestral home for the coronavirus. And in the Science study, rectal swaps taken from two of the beagles exposed to virus did contain viral RNA. But the virus wasn't found in any other tissues.

As of publishing, the United States' Centers for Disease Control and Prevention website offers comfort for those of us who might worry about our own furry companions, let alone the millions of stray Good Boys around the world.

"We do not have evidence that companion animals, including pets, can spread the virus," it reads.

For scientists eager to learn how the coronavirus came into our lives, this study is simply another theory that takes us one step closer to a possible answer. Ultimately, it offers another trail of molecular breadcrumbs that researchers can use to trace the origin of the novel coronavirus.

Abstract: Wild mammalian species, including bats, constitute the natural reservoir of Betacoronavirus (including SARS, MERS, and the deadly SARS-CoV-2). Different hosts or host tissues provide different cellular environments, especially different antiviral and RNA modification activities that can alter RNA modification signatures observed in the viral RNA genome. The zinc finger antiviral protein (ZAP) binds specifically to CpG dinucleotides and recruits other proteins to degrade a variety of viral RNA genomes. Many mammalian RNA viruses have evolved CpG deficiency. Increasing CpG dinucleotides in these low-CpG viral genomes in the presence of ZAP consistently leads to decreased viral replication and virulence. Because ZAP exhibits tissue-specific expression, viruses infecting different tissues are expected to have different CpG signatures, suggesting a means to identify viral tissue-switching events. I show that SARS-CoV-2 has the most extreme CpG deficiency in all known Betacoronavirus genomes. This suggests that SARS-CoV-2 may have evolved in a new host (or new host tissue) with high ZAP expression. A survey of CpG deficiency in viral genomes identified a virulent canine coronavirus (Alphacoronavirus) as possessing the most extreme CpG deficiency, comparable to that observed in SARS-CoV-2. This suggests that the canine tissue infected by the canine coronavirus may provide a cellular environment selecting against CpG. Thus, viral surveys focused on decreasing CpG in viral RNA genomes may provide important clues about the selective environments and viral defenses in the original hosts.