Southeast Asia – a hotspot for SARS-CoV-2-related coronaviruses

Why is understanding the origin of SARS-CoV-2 so important? How do we approach the question and what has been learned?

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Since the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from Wuhan in December 2019, 100 million confirmed cases with greater than 2 million deaths have been reported worldwide. The bat coronavirus RaTG13 was discovered from a Rhinolophus affinis bat sample collected in 2013 and has a genome similarity of 96% to SARS-CoV-2, suggesting that bats are the most likely reservoir for SARS-CoV-2. However, the animal host that carried the progenitor virus for SARS-CoV-2 akin to that of the palm civet for SARS-CoV remains unknown.

Why is this question so important that the World Health Organization (WHO) even started a mission to investigate the origin and early transmission of SARS-CoV-2? There are 3 key reasons for this: one is if the virus is still out there and if we know the source, we would be able to prevent the same virus from reintroducing to the human population. Secondly, if we understand how animal-human spillover events occurred, we would be able to prevent similar events from happening in the future. Last but not least, by understanding how the virus looked like before it jumped to humans, we would be in a better position to map viral evolution and adaption. All in all, investigating the origin of the virus increases our preparedness for emerging and re-emerging infectious diseases.

Rectal swabs were performed on Rhinolophus acuminatus bats by scientists from Chulalongkorn University, Thailand.

In line with WHO’s mission on investigating the origin of SARS-CoV-2, we sampled 100 Rhinolophus acuminatus bats from a Thai cave in June 2020 and discovered a bat coronavirus, named RacCS203, with 91.5% sequence identity to SARS-CoV-2, and 91.4% and 93.7% sequence identity to the bat coronaviruses RaTG13 and RmYN02 discovered in China, respectively. The RacCS203 bat coronavirus is even more similar to SARS-CoV-2 than the Rc-o319 bat coronavirus in Japan published in November 2020, which has a sequence identity of 79.2% to SARS-CoV-2. All these studies suggest that genetically diverse SARS-CoV-2-related coronaviruses are not limited to China and have a geographic distribution spanning over 4,800 kilometers, from Japan all the way to Thailand. Imagine that!

Distribution of Rhinolophus bats hosting SARS-CoV-2-related coronaviruses.

To look for evidence of infection in animals, we tested serum from these R. acuminatus bats as well as pangolins at a wildlife checkpoint in Southern Thailand and were able to detect high levels of neutralizing antibodies against SARS-CoV-2 in these animals. This study adds to a growing body of literature that SARS-CoV-2-related coronaviruses have been circulating in Southeast Asia, where there are large and diverse bat populations. The serological investigations were conducted using the surrogate virus neutralization test (sVNT), named cPass: the first U.S. Food and Drug Administration (FDA)-authorized test for detecting neutralizing antibodies. The test was developed by our group in early 2020 mainly for determining neutralizing antibodies in humans for detecting prior infections and monitoring vaccine efficacy, but it has also proven itself to be extremely useful for tracing the animal origin of the virus. To learn more about how the sVNT was developed and how it works, check out our Nature Biotechnology paper and Behind the Paper post.

Research assistant Ong Xin Mei, Professor Wang Linfa (corresponding author), research assistant Lim Beng Lee (co-author) with the cPass test kits.

In further serological investigations, we found that rabbits immunized with spike protein receptor-binding domain (RBD) of RaTG13 and RmYN02 bat coronavirus were able to produce antibodies that can cross-neutralize and prevent SARS-CoV-2 infection. This is topped by the observation that bat coronavirus RmYN02 does not even bind to the host angiotensin-converting enzyme 2 (ACE2) receptor, which is used by SARS-CoV-2 to enter the cell. This shows how antibodies produced against a SARS-CoV-2-related coronavirus can still potentially protect against SARS-CoV-2.

Without a doubt, there is an incredible underappreciated diversity of viruses in the animal reservoir across Southeast Asia. This calls for systematic, safe, and scientifically advanced surveillance to continually monitor the animal-human interface so that we can have a better understanding of progenitor viral populations circulating in the animal reservoir, as these viruses have a high likelihood of spilling over and making the host switch to humans. This highlights the importance of an open approach to science and working across regional, institutional and governmental boundaries because viruses do not follow boundaries!

Vivian Chih-Wei Chen

MD-PhD Student, Duke-NUS Medical School

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