Colorado State University Led Study Warns That SARS-CoV-2 Variants Rising Rapidly In Non-Human Hosts, Posing A High Risk For Human Reinfection!

A new study led by researchers from  Colorado State University and the University of Pennsylvania School of Veterinary Medicine found that SARS-CoV-2 variants are rapidly emerging in animal hosts with alarming implications of the potential risk for human reinfection!

The SARS-CoV-2 coronavirus spillback from humans into domestic and wild animals has been well-documented. The study team compared variants of cell culture-expanded SARS-CoV-2 inoculum and virus recovered from four species following experimental exposure. Five non-synonymous changes in nsp12, S, N and M genes were near fixation in the inoculum, but reverted to wild-type sequences in RNA recovered from dogs, cats and hamsters within 1-3 days post-exposure. Fourteen emergent variants were detected in viruses recovered from animals, including substitutions at spike positions H69, N501, and D614, which also vary in human lineages of concern. The rapidity of in vitro and in vivo SARS-CoV-2 selection reveals residues with functional significance during host-switching, illustrating the potential for spillback reservoir hosts to accelerate evolution, and demonstrating plasticity of viral adaptation in animal models.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.03.05.434135v2
 
The COVID-19 disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in December 2019 in Wuhan City, China. Virologists believe that the virus jumped from an intermediate animal host to humans.
 
So far the novel coronavirus virus has infected close to 120 million people and killed over 2.65 million worldwide. Hence it is crucial to determine how the virus spreads and evolves to develop vaccines and therapies.
 
The study team found that SARS-CoV-2 variants rapidly emerge in animal hosts, hinting at the potential risk for human reinfection.
 
The new research findings highlight the need to study viral evolution and pathogenesis in human and animal hosts. This could help prevent future outbreaks that may mimic the magnitude of the current COVID-19 pandemic.
 
It has been noted that over the years, cross-species transmission events or spillovers, which challenge pathogens to survive in new host environments, result in species-species adaptations.
 
The SARS outbreak in 2002, the MERS in Saudi Arabia in 2012, and the current COVID-19 pandemic, all emerged from a spillover event. Though bats were most likely the reservoir of coronaviruses, the intermediate hosts include civet cats, camels, and pangolins, among others.
 
Although cross-species transmission events are rare, and in natural settings, they typically fail to result in an epidemic spread, in contrast to most species, humans move globally and regularly come into contact with domestic and peridomestic animals.
 
Hence when a novel virus spreads through human populations, this may cause a spillback into a wide range of companion and wild animals, which has occurred during the current coronavirus pandemic. Given that reverse zoonosis has been reported in animals like cats and dogs from households where people are infected with SARS-CoV-2, the risk of transmitting the virus to animals is plausible.
 
For the study, the research team aimed to assess the evolution of SARS-CoV-2 during three rounds of expansion of strain USA-WA1/2020 in Vero E6 cells, followed by changes happening during the primary experimental infection in four mammalian hosts.
 
The study team compared variants of cell culture-expanded SARS-CoV-2 inoculum and virus recovered from four species following exposure to the virus. They also compared variant proportions, insertions, and deletions occurring in genomes of SARS-CoV-2 obtained from dogs, cats, hamsters, and ferrets.
 
Surprisingly the research team found five chances in nsp12, S, N, and M genes near fixation in the inoculum. Still, it returned to wild-type sequences in the ribonucleic acid (RNA) recovered from the animals about one to three days after exposure.
 
More significantly the study team detected 14 emergency variants in viruses recovered in the animals, including substitutions at spike positions N501, H69, and D614. The speed of in vitro and in vivo SARS-CoV-02 selection shows residues with functional importance during host-switching.
 
Corresponding author Dr Sue VandeWoude from the Department of Microbiology, Immunology, and Pathology at Colorado State University explained to Thailand Medical News, “Pathogens are under strong selective pressure to propagate in the host environment, while host defenses are aligned to prevent pathogen replication.”
 
She added, “This host-pathogen arms race results in varied outcomes that can lead to increases or decreases in virulence and transmission.”
 
The magnitude of cell culture variant reversion was greater in dogs than other species. All five cell culture-associated variants decreased from >93% to to <41%; in particular, D135E and R685H decreased to ≤10%. SARS-CoV-2 was not culturable from canine. Samples, consistent with previous reports, and was below the limit of detection by qPCR, though low level seroconversion suggested some viral replication had occurred. These experimental results contrast with widespread global reports of canine companions becoming infected through contact with their SARS-CoV-2-infected owners. Many variants detected in dogs were not found in the inoculum, reached high frequencies and were under strong selective pressure. The majority of canine variants were found in nonstructural replicase genes, providing strong evidence of selective pressure and host-viral molecular interactions in dogs directed towards selection for viral replication function. The differences between reports of natural reverse-zoonotic infections and laboratory exposures in dogs may stem from disparate doses, dose frequency, or strains (human-adapted or cell culture-propagated virus).
 
Importantly the study findings illustrate the potential for spillback reservoir hosts to hasten evolution. Furthermore, the results highlight the plasticity of viral adaptation in animal models.
 
The study findings may guide researchers to prevent future outbreaks that may emerge in animals and jump to humans.
 
The study team concluded, “Our work additionally illustrates that virus evolution and adaptation following passage in cell culture and experimental infection is far more complex than has typically been acknowledged. The advent of new technologies that afford the opportunity to assess viral quasispecies within inocula and biological samples provides an exciting opportunity for future studies of viral evolution and pathogenesis in both humans and animal hosts.”
 
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