The jury is still out for SARS-CoV-2 intermediate host

By Samantha Black, PhD, The Science Advisory Board staff writer

April 16, 2020 -- Scientists have been searching for the intermediate host between bats, which are known to carry coronaviruses, and the first introduction of SARS-CoV-2 into humans. Conflicting research argues the merit of dogs as intermediate hosts of the virus.

One researcher from the University of Ottawa provides genomic evidence that dogs may be an intermediate carrier, while another study from Chinese researchers suggests that canines would be a poor transmitter of the virus.

Bats are the natural reservoir for betacoronaviruses, a family of viruses that causes such diseases as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and now COVID-19. SARS-CoV-2, the virus that causes COVID-19, shares 96.2% identity at the nucleotide level with the coronavirus RaTG13, which was detected in horseshoe bats in China.

However, many researchers believe that an intermediate host was required in order for SARS-CoV-2 to pass to humans. Many animals could potentially serve as intermediate hosts, such as snakes and pangolins. But researchers have yet to find a definitive answer for this question.

In several new studies, researchers have explored the possibility of dogs as the intermediate host for SARS-CoV-2 from different perspectives and with conflicting results.

Evidence for dogs as intermediate hosts

In an April 15 publication in Molecular Biology and Evolution, a Canadian researcher, Xuhua Xia, PhD, explored how the RNA viral genome of SARS-CoV-2 escapes the viral defenses in humans and how this information can be used to determine the intermediate host of the virus.

The zinc finger antiviral protein (ZAP) is a key component of the human immune response that specifically binds to CpG dinucleotides in viral genomes via an RNA-binding domain, resulting in viral degradation. Some research suggests that ZAP may be the only cellular agent targeting CpG in single-stranded RNA virus genomes, such as coronaviruses. RNA viruses may evolve to have CpG deficiency as a means to avoid targeted ZAP activities. Therefore, Xia suggests that decreased CpG increases the virulence of RNA viruses.

Upon examination of 1,252 full-length betacoronavirus genomes deposited into the GenBank sequence database, Xia found that the closest phylogenetic relative of SARS-CoV-2, the bat coronavirus RaTG13, had the lowest amount of CpG. RaTG13 and SARS-CoV-2 share 96% sequence identity.

Identifying a virus with comparably low CpG levels would suggest that the virus is a common ancestor of BatCoV RaTG13 and SARS-CoV-2. However, of the 1,127 betacoronaviruses available in GenBank at the time, none of them have CpG levels close to that observed in RaTG13 and SARS-CoV-2.

Therefore, researchers examined mammalian hosts with alphacoronavirus genomes for commonality. Canine coronaviruses that cause highly contagious intestinal disease in dogs were found to have similar CpG values as observed in SARS-CoV-2 and RaTG13.

Xia hypothesized that SARS-CoV-2 evolved in the mammalian intestine or tissues associated with the intestine. Many of the early samples of SARS-CoV-2 were isolated from stool samples. This is supported by both the fact that the BatCoV RaTG13 sequence documented in GenBank originated from a fecal swab and that canine coronaviruses cause gastrointestinal disease.

Xia ultimately proposed the following method of transmission of SARS-CoV-2:

  • The ancestor of SARS-CoV-2 and BatCoV RaTG13 infected the intestine of a mammalian species (dogs).
  • The presumably strong selection against CpG in the viral RNA genome in dog intestine resulted in rapid evolution of the virus, leading to reduced CpG levels.
  • The licking of anal regions in dogs facilitated viral transmission from the digestive system to the respiratory system.
  • The reduced viral genomic CpG allowed the virus to evade human ZAP-mediated immune response and become a severe human pathogen.

"While the specific origins of SARS-CoV-2 are of vital interest in the current world health crisis, this study more broadly suggests that important evidence of viral evolution can be revealed by consideration of the interaction of host defenses with viral genomes, including selective pressure exerted by host tissues on viral genome composition," Xia said in a statement.

Evidence against dogs as intermediate hosts

In a different publication, Chinese researchers explored the transmissibility and susceptibility of SARS-CoV-2 in common domestic animals, including ferrets, cats, and dogs.

By inoculating the animals intranasally with the virus (SARS-CoV-2/CTan/human/2020/Wuhan), isolated from a human patient, tissues were collected for viral RNA by qPCR and virus titration in Vero E6 cells. The researchers also explored replication dynamics and transmission of the virus.

In the study, SARS-CoV-2 was found to replicate in the upper respiratory tract of ferrets without causing severe disease or death. The fact that SARS-CoV-2 replicates efficiently in the upper respiratory tract of ferrets makes them a candidate animal model for evaluating antiviral drugs or vaccine candidates against COVID-19.

In cats, viral RNA was detected in many tissues, but not the small intestines. The researchers determined that SARS-CoV-2 can replicate efficiently in cats, with younger cats being more permissive. Perhaps more importantly, the virus can be transmitted between cats via the airborne route.

When dogs were inoculated with SARS-CoV-2 in a similar fashion as ferrets and cats, no viral RNA could be detected in their organs or tissues. The seronegative results indicated that the virus was not infectious to dogs and that they have low susceptibility to SARS-CoV-2.

This study concluded that ferrets and cats are susceptible to SARS-CoV-2 and therefore are useful in vaccine research or disease surveillance, but that dogs are not.

It seems that the jury is still out on the matter of the SARS-CoV-2 intermediate host. More research and definitive answers are needed for this important question.


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