The Paper's reporter He Liping
Since the outbreak of COVID-19, it has not only posed a global threat to public health, but also placed a heavy burden on the health system and the global economy. In response to the pandemic, countries around the world have made unprecedented efforts, including the development of antiviral drugs and vaccination.
Recently, Academician Gao Fu, director of the Chinese Center for Disease Control and Prevention and director of the Key Laboratory of Pathogenic Microbiology and Immunology of the Chinese Academy of Sciences, and others issued a document reminding them that when formulating epidemic prevention and control strategies, a number of factors still need to be paid attention to. The opinion paper was published in the China CDC Weekly under the title "COVID-19 Expands Its Territories from Humans to Animals."
Gao Fu et al. pointed out that in the process of transmission of SARS-CoV-2, several noteworthy variants (VOCs) have gradually been discovered, and current studies have also proved that some of these variants have higher transmission capacity and are more resistant to the neutralizing effect of convalescent and vaccine serum, posing a global threat to public health.
They believe that the arms race between the evolution of SARS-CoV-2 and human coping strategies will continue for some time.
The origin of SARS-CoV-2 remains a mystery
For any epidemic pathogen, tracing the origin of the "main culprit" is critical to understanding its evolution and preventing future outbreaks.
Previous studies have shown that the genome of the bat-derived coronavirus RaTG13 is most similar to SARS-CoV-2 at the genome-wide level (96.2%) compared to SARS-CoV-2, but the amino acid similarity of the spike protein receptor binding domain (RBD) that mediates the virus's entry into human cells is only 89.2%. Subsequently, multiple bat-derived coronavirus genome sequences highly similar to SARS-CoV-2 were also found in different countries.
Multiple studies combined to suggest that SARS-CoV-2 is more likely to come from bats. What the scientific community can determine, however, is that bat-derived coronaviruses need an intermediate host before acquiring enough mutations to have the ability to infect humans, just as the intermediate host for MERS-CoV is a dromedary camel.
Two previous studies have shown that sars-CoV-2-related coronaviruses have been found in Malay pangolins with areas of RBD that are highly similar to SARS-CoV-2. However, overall genomic similarity was lower (<93%) compared to SARS-CoV-2, suggesting that pangolins are unlikely to be intermediate hosts for SARS-CoV-2.
In fact, so far, the pathways by which SARS-CoV-2-related coronaviruses spread from bats to humans and whether bats were the original hosts remain unraveled.
It is worth mentioning that on September 30, Gao Fu led an article in the top medical journal "The Lancet", citing the continuous research progress and experience of the origin of important infectious diseases in the past few decades, providing enlightenment for the prevention and control of unknown diseases, calling for the global depoliticization of the origin of the pathogen of COVID-19, and should be from a scientific point of view with open minds and close international cooperation to trace the root cause of the virus.
In the paper, Gao Fu et al. take the origin of HIV, HKU1 (HCOV-HKU1), SFTSV and MERS-CoV as examples, and propose that tracing the origin of the virus requires long-term and extensive sample accumulation, which may take years or decades. The geographical origin of the virus may not be related to the initial patient, and in some cases, "patient zero" may never be found.
Gao Fu noted that patients with similar symptoms before the pandemic should be re-evaluated, and stored samples in a wide range of areas should be re-tested. Blood banks and tissue banks are an important resource for retrospective serological or genomics research, particularly in countries or regions where evidence of the virus has been present in blood or environmental samples prior to outbreaks. In addition, identifying the natural or intermediate hosts of the virus also requires genome-wide studies of animal samples susceptible to virus infection.
Spillover effects of viruses
In their latest article, Gao Fu et al. wrote that in addition to humans, several other mammals have been found to be naturally infected with SARS-CoV-2 through contact with people with COVID-19, such as cats, dogs, lions and tigers in zoos, mink and ferrets. Snow leopards, mountain lions and gorillas have also been found to be infected with SARS-CoV-2 in nature.
Of these spillover events, the SARS-CoV-2 variant associated with mink had the greatest impact. Previous studies and related reports have made it clear that mink also spread the SARS-CoV-2 variant back to humans and lead to further community transmission. This also means that the spread of the virus between mink and humans forms a "two-way transmission".
In addition, in addition to natural infection cases, infection experiments have also shown that a variety of animals may be susceptible hosts of SARS-CoV-2, such as rabbits, pigs, foxes, civets, etc.
Most of the natural infections mentioned above occur in domestic animals, but far fewer cases are found in wild animals. However, a recent serum surveillance in the United States showed that anti-SARS-CoV-2 antibodies were found in 40% of wild white-tailed deer (Odocoileus virginianus) samples in 2021. Antibodies were detected in 1 and 3 samples in 2019 and 2020, respectively.
Gao Fu et al. pointed out that although it is unclear whether SARS-CoV-2 of wild white-tailed deer was introduced by humans, the sharp increase in antibody positivity rates suggests that SARS-CoV-2 was once transmitted in wild white-tailed deer. Due to the wide geographical distribution of wild white-tailed deer in North America (about 30 million), human contact with wild white-tailed deer can be achieved through wildlife restoration, field research, conservation efforts and some wildlife-related tourism, supplementary feeding, captive deer and hunting activities. In this case, it increases the risk of SARS-CoV-2 from wild animals spreading to humans.
The article also analyzes the molecular mechanism. Mutations at several key sites of RBD and ACE2 of SARS-CoV-2 are closely related to cross-species transmission of the virus. On SARS-CoV-2-RBD, sites 493, 498, and 501 were identified as key mutation hotspots that determine host range.
Amino acids 41 and 42 on ACE2 were identified as key sites for SARS-CoV-2 RBD binding. There are four combinations (Y41-Q42, H41-Q42, Y41-E42 and H41-E42) at these two sites, with the Y41-Q42 combination having the highest binding affinity for SARS-CoV-2 RBD. In addition, K31 and K353 have been reported as mutation hotspots capable of significantly altering binding free energy, and mutations from K353 to A353 may disrupt the binding capacity of ACE2 to SARS-CoV-2-RBD.
Host expansion is not over yet
The article reminds in the final section that the host expansion of the coronavirus has been confirmed. A previous study suggests that some of the ongoing mutations that are adapting to mink pose a huge threat to public health if they spread back to humans and even trigger further community transmission.
Since mink is farmed, large-scale slaughter of mink can effectively prevent the spread and mutation accumulation of mink source SARS-CoV-2 mutations in mink populations. However, similar measures cannot be taken with regard to wildlife.
Adaptive mutations are needed when cross-species transmission occurs and spreads within new host populations, so more effort is needed to investigate the genetic alterations of these new variants of wild white-tailed deer and the corresponding effects of transmission and contagion on humans.
In particular, because SARS-CoV-2 is spreading to wild animals, many other wild animals can also be infected with SARS-CoV-2 through direct or indirect contact with wild white-tailed deer. Some experimental studies have shown that some animals may be susceptible to SARS-CoV-2, such as Egyptian fruit bats, common marmosets, macaques, embankment voles, and North American deer rats. However, these are just the tip of the iceberg, as the susceptibility of most terrestrial wildlife to SARS-CoV-2 has not yet been tested.
It is also worth noting that research on the susceptibility of marine wildlife, especially marine mammals, to SARS-CoV-2 is almost blank. Due to the high frequency of human marine activities (e.g. mariculture, marine fishing), the frequency of human contact with marine life is high. If certain marine organisms are highly sensitive to SARS-CoV-2, there is a risk of transmission from humans to marine life.
More seriously, SARS-CoV-2 may spread in marine ecosystems, leading to the emergence of some new SARS-CoV-2 variants that pose an unknown threat to humans.
"Therefore, it is necessary to conduct large-scale SARS-CoV-2 screening of terrestrial and marine wildlife, especially susceptible wildlife, to monitor their infection and mutation and develop further prevention and control strategies." Gao Fu et al. believe that this also provides more clues for studying the origin and cross-species transmission of SARS-CoV-2.
Editor-in-Charge: Li Yuequn