New evidence of stray dogs as possible origin of COVID-19 pandemic

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In a new study, researchers found new evidence of stray dogs as a possible origin of COVID-19 pandemic.

They traced coronavirus across different species and found that stray dogs—-specifically dog intestines—- may have been the origin of the current SARS-CoV-2 pandemic.

They say the ancestor of SARS-CoV-2 and its nearest relative, a bat coronavirus, infected the intestine of canids, most likely resulting in rapid evolution of the virus in canids and its jump into humans.

This suggests the importance of monitoring SARS-like coronaviruses in feral dogs in the fight against SARS-CoV-2.

The research was conducted by a team at the University of Ottawa.

Ever since the outbreak of the COVID-19, scientists have been scrambling to identify the species of origin to understand how the new coronavirus first leaped from its animal hosts to humans, causing the current pandemic infecting more than a million people worldwide.

Scientists have been looking for an intermediate animal host between bats, which are known to harbor many coronaviruses, and the first introduction of SARS-CoV-2 into humans.

Many animals, beginning with snakes and most recently, pangolins, have all been put forth as the likely intermediate, but the viruses isolated from them are too divergent from SARS-CoV-2, suggesting a common ancestor too far back in time—-living in the 1960s.

Humans and mammals have a key antiviral sentinel protein, called ZAP, which can stop a virus in its tracks by preventing its multiplication in the host and degrading its genome.

The viral target is a pair of chemical letters, called CpG dinucleotides, within its RNA genome.

CpG dinucleotides act as a signpost that a person’s immune system uses to seek and destroy a virus. ZAP patrols human lungs and is made in large amounts in the bone marrow and lymph nodes, where the immune system first primes its attack.

But it’s been shown that viruses can punch back. Single-stranded coronaviruses, like SARS-CoV, can avoid ZAP by reducing these CpG signposts, thus rendering ZAP powerless.

A similar examination of HIV, another RNA virus, shows that it has also exploited this evolutionary trick to lose CpG in response to human antiviral defenses.

One implication of this is that the remaining CpG dinucleotides on the viral genome are likely functionally important for the virus and could serve as the target of modification to attenuate virulence in vaccine development.

To perform the study, the team examined all 1252 full-length betacoronavirus genomes deposited into GenBank to date.

They found that SARS-CoV-2 and its most closely related known relative, a bat coronavirus (BatCoV RaTG13), have the lowest amount of CpG among its close coronavirus relatives.

The team used their CpG tool to reexamine the camel origin of MERS, and found those viruses infecting camel digestive system also had lower genomic CpG than those infecting camel respiratory system.

When they examined the data in dogs, he found that only genomes from canine coronaviruses (CCoVs), which had caused a highly contagious intestinal disease worldwide in dogs, have genomic CpG values similar to those observed in SARS-CoV-2 and BatCoV RaTG13.

Second, canids, like camels, also have coronaviruses infecting their digestive system with CpG lower than those infecting their respiratory system (canine respiratory coronavirus or CRCoV belonging to BetaCoV).

In addition, the known cellular receptor for SARS-CoV-2 entry into the cell is ACE2 (angiotensin I converting enzyme 2).

ACE2 is made in the human digestive system, at the highest levels in the small intestine and duodenum, with relatively low expression in the lung.

This suggests that mammalian digestive systems are likely to be a key target infected by coronaviruses.

Humans are the only other host species to produce coronavirus genomes with low genomic CpG values.

In a comprehensive study of the first 12 COVID-19 patients in the U.S., one patient reported diarrhea as the initial symptom before developing fever and cough, and stool samples from 7 out of 10 patients tested positive for SARS-CoV-2, including 3 patients with diarrhea.

Canids are often observed to lick their anal and genital regions, not only during mating but also in other circumstances.

Such behavior would facilitate viral transmission from the digestive system to the respiratory system and the interchange between a gastrointestinal pathogen and a respiratory tract and lung pathogen.

Based on his results, the team presents a scenario in which the coronavirus first spread from bats to stray dogs eating bat meat.

Next, the presumably strong selection against CpG in the viral RNA genome in canid intestines resulted in the rapid evolution of the virus leading to reduced genomic CpG.

Finally, the reduced viral genomic CpG allowed the virus to evade human ZAP-mediated immune response and became a severe human pathogen.

The lead author of the study is biology professor Xuhua Xia.

The study is published in Molecular Biology And Evolution.

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