Origin of SARS-CoV-2
Based on the studies of SARS-CoV and MERS-CoV transmission, SARS-CoV-2 is thought to have originated in bats. Research at the Wuhan Institute of Virology has demonstrated that SARS-CoV-2 has 96% genetic sequence homology with coronavirus strain RATG13, that was collected from bats in the same cave in Yunnan, China. The route by which SARS-CoV-2 evolved to become transmissible from bats to humans, has not been determined.
Compared to other coronaviruses, the spike protein of SARS-CoV-2 has become optimized for binding to the ACE2 receptor on human cells with high affinity and it has obtained a functional polybasic cleavage site at the junction of the S1 and S2 subunits of the spike. The latter feature enhances cleavage of the spike protein by cell proteases, such as furin, and increases viral infectivity. SARS-CoV-2 is unlikely to have been transmitted directly from bats to humans, because bat coronaviruses lack these two features.
Two different scenarios have been proposed to explain the origin of SARS-CoV-2; (1) natural selection in an animal host before zoonotic transfer to humans and (2) natural selection in humans following zoonotic transfer.
Different coronaviruses infecting the same host can exchange gene segments. If a bat virus like RATG13 co-infected an animal already infected with another coronavirus which possessed an RBD more adept at infecting humans, SARS-CoV-2 could have arisen by genetic recombination. In this scenario, the RBD of the SARS-CoV-2's spike protein evolved to its current state in another animal prior to infecting humans. The pandemic would have emerged rapidly as soon as humans were infected, because the virus had already evolved to become highly infectious.
The second scenario proposes that a non-pathogenic version of the virus jumped from an animal host into humans and then evolved to its current pathogenic state. For instance, some coronaviruses from pangolins have a nearly identical RBD structure very similar to that of SARS-CoV-2. A coronavirus from a pangolin could possibly have been transmitted to a human. Pangolins are highly valued for traditional Chinese medicine and sold in markets such as Wuhan Seafood and Wildlife Market, where many early human cases occurred
SARS-CoV-2 could have evolved further within a human host by obtaining genetic material from another unrelated virus. For example, some avian influenza viruses have a polybasic cleavage site that is structurally similar to SARS-CoV-2. If a person became coinfected with SARS-CoV-2 and avian influenza, genetic recombination could have occurred creating a modification that made SARS-CoV-2 even more capable of spreading between people.
Several other provocative theories have arisen which propose that SARS-CoV—2 was created in The Wuhan Institute of Virology where basic research on bat coronaviruses has been performed for many years. These theories suggest that the virus was either intentionally or accidentally released into the surrounding community.
The Wuhan Laboratory has performed research recombining the genomes of coronaviruses from different species to determine their potential to infect human cells. SARS-CoV-2 might have acquired RBD mutations during passage in cell culture or acquired a pangolin RBD via genetic recombination. However, it would have also then had to acquire the polybasic cleavage site of the spike protein by repeated passage in cell cultures or animals infected with avian influenza virus. Prominent virologists in the United States think it is highly unlikely that both of these unique features could have been acquired in tissue culture.
This type of research is performed in Biosafety Level 4 (BSL-4) laboratories, which provide the highest level of biocontainment. They follow the most stringent biosafety protocols including sophisticated airflow systems, sealed containers, positive-pressure personal protective equipment (PPE), extensive training, and tightly controlled building access.
However, these precautions do not dismiss the need for constant surveillance of these facilities. Leakage of pathogens from these types of laboratories have been documented on several occasions. The world’s last known case of smallpox was caused by a leak from a British laboratory in 1978. An outbreak of foot and mouth disease in 2007 had a similar origin. Laboratories in the United States have had accidental releases of Ebola and a deadly strain of avian influenza. Chinese laboratory workers have been infected with SARS-CoV and transmitted it to outside contacts on at least two occasions.
Today, there are approximately 70 BSL-4 laboratories in 30 countries. More facilities are being planned. Many scientists fear that with so many biologists actively hunting for bat viruses, and gain-of-function work becoming more common in these laboratories, the world might be at increasing risk of a laboratory-derived pandemic in the future.
References
Andersen KG et al. The proximal origin of SARS-CoV-2, Nature Medicine published online 17 March, 2020. https://doi.org/10.1038/s41591-020-0820-9
Van Beusekom, M. Scientists: Exactly zero evidence COVID19 came from a lab. CIDRAP, May 12, 2020, https://www.cidrap.umn.edu/news-perspective/2020/05/scientists-exactly-zero-evidence-covid-19-came-lab
The pieces of the puzzle of covid-19’s origin are coming to light. The Economist, May 2, 2020
