Evolution of pandemic coronavirus outlines path from animals to humans
The virus's ability to change makes it likely that new human coronaviruses will arise
DURHAM, N.C. -- A team of scientists studying the origin of SARS-CoV-2, the virus that has caused the COVID-19 pandemic, found that it was especially well-suited to jump from animals to humans by shapeshifting as it gained the ability to infect human cells.
Conducting a genetic analysis, researchers from Duke University, Los Alamos National Laboratory, the University of Texas at El Paso and New York University confirmed that the closest relative of the virus was a coronavirus that infects bats. But that virus's ability to infect humans was gained through exchanging a critical gene fragment from a coronavirus that infects a scaly mammal called a pangolin, which made it possible for the virus to infect humans.
The researchers report that this jump from species-to-species was the result of the virus's ability to bind to host cells through alterations in its genetic material. By analogy, it is as if the virus retooled the key that enables it to unlock a host cell's door -- in this case a human cell. In the case of SARS-CoV-2, the "key" is a spike protein found on the surface of the virus. Coronaviruses use this protein to attach to cells and infect them.
"Very much like the original SARS that jumped from bats to civets, or MERS that went from bats to dromedary camels, and then to humans, the progenitor of this pandemic coronavirus underwent evolutionary changes in its genetic material that enabled it to eventually infect humans," said Feng Gao, M.D., professor of medicine in the Division of Infectious Diseases at Duke University School of Medicine and corresponding author of the study publishing online May 29 in the journal Science Advances.
Gao and colleagues said tracing the virus's evolutionary pathway will help deter future pandemics arising from the virus and possibly guide vaccine research.
The researchers found that typical pangolin coronaviruses are too different from SARS-CoV-2 for them to have directly caused the human pandemic.
However, they do contain a receptor-binding site -- a part of the spike protein necessary to bind to the cell membrane -- that is important for human infection. This binding site makes it possible to affix to a cell surface protein that is abundant on human respiratory and intestinal epithelial cells, endothelial cell and kidney cells, among others.
While the viral ancestor in the bat is the most closely related coronavirus to SARS-CoV-2, its binding site is very different, and on its own cannot efficiently infect human cells.
SARS-CoV-2 appears to be a hybrid between bat and pangolin viruses to obtain the "key" necessary receptor-binding site for human infection.
"There are regions of the virus with a very high degree of similarity of amino acid sequences among divergent coronaviruses that infect humans, bats and pangolins, suggesting that these viruses are under similar host selection and may have made the ancestor of SARS-CoV-2 able to readily jump from these animals to humans," said lead co-author Xiaojun Li from Duke.
"People had already looked at the coronavirus sequences sampled from pangolins that we discuss in our paper, however, the scientific community was still divided on whether they played a role in the evolution of SARS-CoV-2," said study co-lead author Elena Giorgi, staff scientist at Los Alamos National Laboratory.
"In our study, we demonstrated that indeed SARS-CoV-2 has a rich evolutionary history that included a reshuffling of genetic material between bat and pangolin coronavirus before it acquired its ability to jump to humans," Giorgi said.
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In addition to Gao, Li and Giorgi, study authors include, Manukumar Honnayakanahalli Marichannegowda, Brian Foley, Chuan Xiao, Xiang-Peng Kong, Yue Chen, S. Gnanakaran and Bette Korber
SARS-CoV-2 possibly emerged from shuffling and selection of viral genes across different species
Emergence of SARS-CoV-2 through recombination and strong purifying selection
A combination of genetic shuffling and evolutionary selection of near-identical genetic sequences among specific bat and pangolin coronaviruses may have led to the evolution of SARS-CoV-2 and its introduction into humans, a new study suggests. The results also showed that the virus' entire receptor binding motif (RBM), a component that plays a key role in viral entry into host cells, was introduced through recombination with pangolin coronaviruses. The study joins ongoing efforts to identify the source of the virus that causes COVID-19, which is critical for informing efforts to establish proper animal models, discover new drugs and vaccines, and ultimately prevent the rise of future zoonotic diseases. While the precise origin of SARS-CoV-2 remains a mystery, this study makes clear "that reducing or eliminating direct human contact with wild animals is critical to preventing new coronavirus zoonoses in the future," the authors say. Proximity of different species in a wet market setting, for example, may increase the potential for cross-species spillover infections, by enabling recombination between more distant coronaviruses and the emergence of mutations, the authors say. By analyzing 43 complete genome sequences from three strains of SARS-CoV-2-like coronaviruses from bats and pangolins, Xiaojun Li and colleagues delineated which strains were most and least similar to the novel coronavirus, with a special focus on genes related to the virus' spike protein complex, a critical component that facilitates viral entry into host cells. They found evidence of strong evolutionary selection around the RBM - part of the spike's amino acid sequence that directly contacts host cell receptors - among the bat, pangolin, and human coronaviruses they studied. Amino acid sequences from these viruses and SARS-CoV-2 were identical or nearly identical in the regions adjacent to the RBM, suggesting that common evolutionary mechanisms shaped these distinct viral strains. The scientists also demonstrated that SARS-CoV-2's entire RBM was introduced through recombination with coronaviruses from pangolins. Together, evolutionary selection and frequent recombination among coronaviruses from bats, pangolins, and humans may have allowed the closely related viruses to readily jump between species, the authors postulate, leading to the introduction of SARS-CoV-2 in humans.
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