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COVID Virus a Genetic Cousin of Scaly Mammal Coronavirus
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Mark Mascolini
Genetic sequences of SARS-CoV-2, the COVID-19 virus, strikingly resemble sequences of a coronavirus found in pangolins, heavily trafficked scaly mammals that look like anteaters [1]. Humans avidly hunt pangolins and smuggle them into China, where their meat ranks as a delicacy and their scales hold purported medicinal powers [2]. Researchers in Guangzhou who discovered the pangolin coronavirus warn that the virus "could represent a future threat to public health if wildlife trade is not effectively controlled." But they do not believe the pangolin coronavirus led directly to SARS-CoV-2 infection in humans.
Because the bat coronavirus RaTG13 has a gene sequence 96% similar to that of SARS-CoV-2, many consider bats the main reservoir for the COVID-19 virus [3]. But how the bat coronavirus made its way to humans remains uncertain. Some suspect it emerged accidentally from a high-security biosafety lab that studied bat coronaviruses in Wuhan, epicenter of the COVID-19 epidemic. Alternatively, early research found that many of the first people infected with SARS-CoV-2 may have picked it up at a Wuhan wet market, where vendors sell fresh meat, fish, fruit, and vegetables [4]. There is no apparent link between bats and the wet market, so how would a coronavirus get to that market?
Pangolins seemed a plausible suspect, because of high (illegal) demand for their savory meat and medicinal—even magical—scales [2]. Inventories at the Wuhan wet market do not list pangolin meat or scales, but perhaps the rare mammal got left off those lists because selling pangolins in China can earn you 10 years in prison [3].
Now researchers from South China Agricultural University in Guangzhou have published gene sequence data suggesting a pangolin coronavirus they call Pangolin-CoV could have merged with bat RaTG13-like virus as a step in the evolution of SARS-CoV-2 [1]. Their report in the esteemed journal Nature does not explain if SARS-CoV-2 found its way to the Wuhan wet market or reveal another route to humans in Wuhan. But their results show marked genetic similarities between a pangolin coronavirus and SARS-CoV-2.
The investigators started with a Blast search for SARS-related CoV (SARSr-CoV) in mammals and birds, finding 34 highly related overlapping viral sequences (contigs) in pangolins. Narrowing their search to this prehistoric-looking mammal, they focused on lung tissue from 4 Chinese pangolins and 25 Malayan pangolins living at a wildlife rescue center in March-August 2019. Using an RT-PCR assay, they recovered SARSr-CoV from 17 of the 25 Malayan pangolins and none of the 4 Chinese animals.
The 17 pangolins that tested positive gradually showed signs of respiratory disease, including shortness of breath, lack of appetite, emaciation, inactivity, and crying. Fourteen of those 17 animals died within 1.5 months. Next the Guangzhou team isolated coronavirus from one of the pangolins that died and analyzed genes that coded for the viral spike and RNA-dependent RNA polymerase (RdRp) regions. The spike genes had a nucleotide sequence 84.5% the same as SARS-CoV-2, and the RdRp genes proved 92.2% similar to SARS-CoV-2. The investigators determined that the E, M, N, and S genes of Pangolin-CoV had amino acid sequences 100%, 98.6%, 97.8%, and 90.7% similar to those SARS-CoV-2 genes.
Further analysis at the whole-genome level showed that Pangolin-CoV shared 80% sequence identity with SARS-CoV-2 and 98% identity with bat RaTG13 coronavirus, except for the S gene. Detailed scrutiny of the S gene yielded evidence suggesting that SARS-CoV-2 may have evolved from recombination of Pangolin-CoV-like virus with bat RaTG13-like virus.
Because SARS-CoV-2 has a gene sequence about 96% similar to that of bat RaTG13, the Guangzhou investigators believe "it is reasonable to assume that bats are the native host of SARS-CoV-2," as others have proposed for SARS-CoV-1 and MERS-CoV, two other disease-causing human coronaviruses. Although their study suggests pangolins may provide a reservoir of SARS-CoV-2-like viruses, the animals are probably "an intermediate host" for SARS-CoV-2 because "a natural reservoir host does not show severe disease," as infected pangolins did in this study.
The authors note that an "insatiable demand" for pangolin meat and use of their scales in traditional Chinese medicine have made illegal smuggling of pangolins "rampant." They called for "stricter regulations against illegal wildlife trade and consumption of game meat" to protect endangered wildlife and prevent "major outbreaks" of infection with SARS-related coronaviruses.
References
1. Xiao K, Zhai J, Feng Y, et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature. 2020 May 7. doi: 10.1038/s41586-020-2313-x. https://www.nature.com/articles/s41586-020-2313-x
2. American Wildlife Foundation. Pangolin. https://www.awf.org/wildlife-conservation/pangolin
3. Cyranoski D. Did pangolins spread the China coronavirus to people? Nature. February 7, 2020. https://www.nature.com/articles/d41586-020-00364-2
4. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199-1207. doi: 10.1056/NEJMoa2001316.
The SARSr-CoV virus identified in the present study and the metagenomic assemblies of viral sequences from Malayan pangolins14 are genetically related to SARS-CoV-2, but are unlikely directly linked to the outbreak because of its substantial sequence differences from SARS-CoV-2.
A virus related to Pangolin-CoV, however, appears having donated the RBD to SARS-CoV-2. SARSr-CoV sequences were previously detected in dead Malayan pangolins15. These sequences appear to be from Pangolin-CoV identified in the present study judged by their sequence similarity. In the present study, we have provided evidence on the potential for pangolins as the zoonotic reservoir of SARS-CoV-2-like coronaviruses. However, these pangolins showed clinical signs of disease. Generally, a natural reservoir host does not show severe disease, while an interme-diate host may have clinical signs of infection16. Because of the lack of evidence from immunohistochemistry or in situ hybridization experi-ments, although a SARS-CoV-2-like coronavirus was detected in the lung of these pangolins, a direct association between the clinical signs or pathology and active virus replication is still not available. Experimental infection of healthy pangolins with pangolin-CoV would give us more definitive answers. However, pangolins are protected animals, making it difficult to carry out such experiments. Further studies are needed to confirm their roles in the transmission of SARSr-CoVs.As the RBD of Pangolin-CoV is virtually identical to that of SARS-CoV-2, the virus in pangolins presents a potential future threat to public health. Pangolins and bats are both nocturnal animals, eat insects, and share overlapping ecological niches17,18, which make pangolins the ideal inter-mediate host for some SARSr-CoV. Therefore, more systematic and long-term monitoring of SARSr-CoV in pangolins and other related animals should be implemented to identify the potential animal source of SARS-CoV-2 in the current outbreak.Findings in the study support the call for stronger ban of illegal pan-golin trade. Due to the insatiable demand for their meat as a delicacy and scales for use in traditional medicine in China, the illegal smuggling of other pangolins from Southeast Asia to China is rampant18. Interna-tional co-operation and stricter regulations against illegal wildlife trade and consumption of game meat should be implemented. They can offer stronger protection of endangered animals as well as the prevention of major outbreaks caused by SARSr-CoVs.
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