The new findings "provide strong evidence for the natural origin of the coronavirus, suggesting that wildlife such as bats in nature may carry more similar viruses." ” | Image source: pixabay.com
Introduction
A study by the Pasteur Institute and the Lao National University suggests that coronaviruses that can infect humans are likely to spread widely among bats in Southeast Asia, as evidenced by three newly discovered bat coronaviruses in Laos that are highly similar to the coronavirus.
Written by | Jacques Hill
Responsible editor| Feng Hao and Chen Xiaoxue
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Since the outbreak of the epidemic in 2019, the origin of the new crown virus has received widespread attention from the scientific community and the general public [1]. The mainstream research method to trace the origin of the new crown virus is to look for coronaviruses carried by wild animals that are similar to the sequence of the new crown virus. Currently reported, the coronavirus most similar to the whole genome sequence of the new coronavirus is RaTG13 detected in Rhinolophus affinis [2, 3], and its evolutionary divergence from the new coronavirus occurred more than 50 years ago [4].
Scientists generally believe that the key to determining the host range of coronaviruses is the spike protein, specifically its receptor-binding domain.
According to existing research, the spike protein of bat coronavirus RaTG13 binds to human receptors less efficiently and the virus's ability to infect human cells is very limited [5]. The receptor-binding domain sequence of the pangolin coronavirus is closer to that of the new coronavirus [6, 7] and has the ability to infect human cells [8].
Therefore, scientists once judged that the new crown virus may be recombined in the receptor binding domain through bat coronavirus and pangolin coronavirus, and pangolin may be the intermediate host for the new coronavirus to be transmitted from bats to humans.
Researchers at the Institut Pasteur in France, the Institut Pasteur in Laos and the Lao National University believe that if the new coronavirus is directly "spilled" by bats to humans, it should be possible to detect coronaviruses in wild bats that are similar to the sequence of the binding domain of the new coronavirus receptor.
To test this hypothesis, they collected 1,551 bat blood, saliva, swab/feces, and urine samples from caves in the karst (karst) landscape of northern Laos and performed coronavirus genome sequence analysis [9]. On September 17, 2021, they uploaded the findings to Nature's preprint platform (not yet peer-reviewed).
In the samples collected, the researchers found that three bat coronaviruses (BANAL-52, BANAL-103 and BANAL-236) were highly similar to the coronavirus sequence. Among them, BANAL-52 is second only to RaTG13 (Figure A) among all reported coronaviruses.
"The virus found in this article is the closest ancestor of the new coronavirus found so far, providing strong evidence for the natural origin of the new coronavirus, and that wild animals such as bats in nature may carry more similar viruses." In an interview with The Intellectual, Shi Zhengli, a researcher at the Wuhan Institute of Virology at the Chinese Academy of Sciences, said.
Of particular note is that of the 17 amino acids that come into contact with human receptors in the receptor-binding domain of spike proteins, BANAL-52 and BANAL-103 have 16 amino acids identical to the new coronavirus (Figure B). In stark contrast, RaTG13 has only 11 amino acids of the same amino acids as the coronavirus.
The study found that unlike the widely reported bat coronavirus RaTG13, the newly discovered spike protein of bat coronavirus can bind to human cell receptors, can mediate virus infection with human cells, and can be neutralized by new coronavirus antibodies in human serum.
Jin Dongyan, a professor at the School of Biomedical Sciences at the University of Hong Kong's Li Ka Shing School of Medicine, believes that the discovery is "basically known or expected", and at the genome-wide level, the newly discovered three bat viruses have not shown closer to the new crown virus than RaTG13.
The evolutionary tree of the new coronavirus and its related viruses. (A) Genome-wide (B) based on sequences containing spike protein receptor binding domains | Source: Literature[9]
The study found that the sequences of coronaviruses carried by different bat species in the same cave are highly similar, indicating that the coronavirus can spread between multiple bat species in the same cave, providing conditions for the recombination of bat coronaviruses of different origins. Therefore, the new crown virus may be produced through the recombination of coronaviruses derived from multiple bat species.
In this regard, Zhu Huachen, deputy director of the Joint Institute of Virology of Shantou University and the University of Hong Kong/Guangdong-Hong Kong Joint Laboratory of Emerging Infectious Diseases, explained that bats are like a large reservoir, storing a large number of coronaviruses with high genetic diversity, and it is now known that most mammalian coronaviruses can be found in bats with coronaviruses with genetic associations, and sometimes various recombinations occur between these viruses, resulting in some new variants.
Compared with the pangolin coronavirus, the newly discovered bat coronavirus has a more similar sequence of receptor-binding domains to the new coronavirus. Unlike studies that support pangolins as intermediate hosts involved in the origin of the coronavirus, this study supports that coronaviruses can be directly "spilled" from bat hosts to infect humans. This conclusion is also consistent with recent results of traceability of the new coronavirus based on mutational characteristics [10,11].
If the coronavirus "spills" directly from bats, how does it spread to humans? Researchers believe that monks practicing in or near caves, tourists entering caves, or related practitioners working in caves may be directly exposed to bat coronavirus.
In addition, the study expanded the understanding of the natural distribution of coronavirus in different countries and regions. Zhu Huachen said that before, in Yunnan, Zhejiang, China, as well as Japan, Cambodia, Thailand and other places, the coronavirus has been found. This study tells us that this type of virus is also present in bat swarms in northern Laos. "Perhaps, in the limestone cave system of the Indochina Peninsula, in several countries across the banks of the Mekong River, and even in other countries and regions that have not yet been noticed, there may be traces of such viruses in the wild."
The presence of a flynn protease cleavage site in the spike protein of the new coronavirus can improve the efficiency of the virus entering the host cell. The study found no flynn protease cleavage site in the newly collected bat virus samples, and the researchers interpreted that the current bat coronavirus sample volume is still insufficient.
Jin Dongyan also pointed out that the study still needs to be improved, and many specific data have not been given, for example, the homology comparison between the newly discovered virus and RaTG13, the homology comparison of the receptor binding domain, and so on.
In an interview, Professor Eddie Holmes, an evolutionary biologist and virologist at the University of Sydney, noted that "research adds convincing evidence to the natural origins of the coronavirus, highlighting the widespread presence of coronaviruses with the ability to infect humans" [12]. Jin Dongyan believes that "as far as the traceability of the virus is concerned, finding a virus close to the same as the new crown in animals and excluding humans can be regarded as truly finding the source of the new crown virus."
In the future, researchers will need to investigate the population around the bat cave to assess whether they have been infected with bat coronavirus and whether they have produced coronavirus-related antibodies. Zhu Warns that coronaviruses have a natural ability to spread across species, and the infections they cause are not accidental one-time events; at least in the genus Chrysanthemum Bat, its infection and epidemic are "natural events" that can occur repeatedly. "This reminds us that there will be more species in nature that are naturally poisonous and have not yet been discovered, like the chrysanthemum bat and pangolin?"
"These results will provide direction for subsequent traceability of the new crown virus, highlighting the importance of prospective research on virus-carrying in wild animals and early warning of the risk of cross-species infection." Shi Zhengli said.
Resources
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12. https://www.bloomberg.com/news/articles/2021-09-18/bats-in-laos-caves-harbor-closest-relatives-to-covid-19-virus