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Using cats as an animal model to study the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the researchers determined that the virus has a narrow transmission bottleneck.
The current 2019 coronavirus (COVID-19) pandemic, caused by the agent SARS-CoV-2, is widely believed to be zoonotic in origin (meaning it originated in animals and has since passed on to human hosts). Much scientific research has subsequently been directed towards understanding the genetic diversity of RNA viruses, such as SARS-CoV-2.
An animal model is useful for studying viral genetic variation in the host and between different hosts. SARS-CoV-2 animal models included Syrian hamsters, ferrets, cats and dogs, among which natural transmission was only observed in minks, cats and ferrets. Only in cats, however, was SARS-CoV-2 detected in the lower respiratory tract; infection in this region for humans has been linked to severe cases of COVID-19.
Transmission bottleneck
The term transmission bottleneck refers to a significant reduction in the virus population during transmission. Observing the development of transmission bottlenecks is important for understanding the evolution of respiratory viruses. Tight transmission bottlenecks, where there is weak natural selection, could reduce adaptations in the seasonal influenza virus and could also play a role in the transmission of SARS-CoV-2. An accurate understanding of the size of the SARS-CoV-2 transmission bottleneck could therefore help predict its evolution.
Since previous human studies on the transmission bottleneck have reported mixed results, a new study used a cat model. The results of the study are available on bioRxiv*, the prepress server
SARS-CoV-2 genetic diversity in cats
The researchers, from the University of Wisconsin-Madison and Emory University in the United States, used genome sequencing of the virus in index cats, cats first infected with the virus, and other cats to whom index cats transmitted the virus. . They then studied the changes in these sequences over time to determine the genetic variation.
They inoculated three domestic cats with a human isolate SARS-CoV-2 from Tokyo. Each inoculated cat was then kept with a virus-free cat, starting the day after inoculation. They then collected nasal swabs every day for up to 10 days.
Experimental chronology. Schematic representing the sampling timeline for the three transmission pairs. The index cats were inoculated on day 0 with 5.2e5 ELTs from a human isolate (hCoV-19 / Japan / UT-NCGM02 / 2020) and were housed together with a naive cat starting on day 1. Inside of each transmission pair, the top row of circles represent the cat index and the bottom row represents the contact cat. Open circles represent days when no detectable infectious virus was found as indicated by the plaque test, while closed circles highlight days when live virus was recovered. Circles with a red outline indicate the time points used in the betabinomal estimation to calculate the size of the transmission bottleneck.
They found that 86% of the variants were found in a single cat, 8% in 2-5 cats, and the remaining variants were found in all six cats. Approximately 43% of the mutations occurred with a frequency of 3 to 10% and approximately 8% occurred with a frequency of 40-50%, with the frequency of changes having remained approximately the same over time in cats index.
Purifying selection occurs when harmful mutations are removed and result in multiple low frequency variants. Positive selection results in higher frequency variations and is when useful variations are retained in the population. Since about half of the variants occur at low frequency, purifying selection is predominant in cats. By comparing non-synonymous and synonymous nucleotide diversity, the authors found that genetic variations in index cats were driven by genetic drift, or mutations that occurred by chance.
To determine the size of the transmission bottleneck in cats, the authors investigated the amount of genetic diversity lost after transmission. They found fewer variants in contact cats than its cat index. Furthermore, they found that the actual size of the bottleneck was five (after two and three days, respectively, index and contact cat); three (after five and six days); and two (after four and five days). This is similar to other studies on the transmission of the influenza virus in humans.
The mutation rate of SARS-CoV-2 in cats is slow
Although the genetic variation within the hosts was low, there were two notable mutations. One, variant S H655Y, has been seen before and is related to the fusion of the spike protein glycoprotein. The other variant, E S67S, hasn’t been seen before. Both variants were transmitted in two of the three cats.
The results suggest that genetic selection within hosts is weak and the transmission bottleneck is tight, even during close contact, indicating that SARS-CoV-2 is perhaps already well adapted to mammalian hosts.
“The strong role of genetic drift can combine with the relatively slow mutation rate and tight transmission bottlenecks to slow the overall pace of viral evolution,” the authors write.
The narrow transmission bottleneck conflicts with some human studies. However, the authors suggest that the experimental design of the current study avoids the challenges faced in previous human studies; that is, the potential for other sources of exposure to the infection and not just intra-family transmission.
There have been reports of natural transmission from humans to cats, so cats could be a feasible model for studying the genetic diversity of viruses. The narrow transmission bottleneck suggests that variations in SARS-CoV-2 that could affect innate immunity or antivirals could be slow.
However, variants arise early and are capable of being passed on in cats, a potential reservoir species, and host-specific adaptations are also inevitable in SARS-CoV-2. This can also affect humans when exposed to species-specific adaptations, requiring ongoing studies on sequencing and understanding the SARS-CoV-2 genetic diversity in different hosts.
*Important Notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as consolidated information.
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