Although the origin of the new coronavirus remains inconclusive, according to the analysis of existing genomic data, the scientific community has drawn preliminary conclusions that bats may be the reservoir species for the novel coronavirus (SARS-CoV-2). If this view is proved to be credible, how does the virus jump from a bat to a human? With the development of the pandemic, the novel coronavirus (SARS-CoV-2) has demonstrated its power to infect human beings with continuous improvement. Herein, we discuss how the coronavirus has been transferred from bats to humans, why SARS-CoV-2 is so deadly, and explore whether it may disappear someday.
Figure-1 The Spread of the SARS-CoV-2: from bats to human
(Thamina Acter et al., 2020）
As the only mammals that are naturally capable of sustained flight, bats are the perfect hosts for a lot of disease-causing viruses that can be transferred to other species including humans, such as, SARS (Severe acute respiratory syndrome), MERS (Middle East Respiratory Syndrome), Ebola and the novel coronavirus (SARS-CoV-2). First, we will analyze the coronavirus in detail.
As a coronavirus, the evolution of SARS-CoV-2 is a natural event that has been anticipated by virologists. As early as the outbreak of SARS and MERS, some scholars began to study the coronavirus. However, because the outbreak of SARS came and went quickly, many related the virus research projects stopped abruptly. Additionally, since MERS did not trigger a global panic, this led to limited development on the understanding of this coronavirus. Once the novel coronavirus disease (COVID-19) spread quickly across the globe in January 2020, scholars and scientists started to evaluate and discuss the epidemic situation. Since then, COVID-19 has been of utmost concern to the public, in addition to the scientists working on SARS-CoV-2/COVID-19 research. With new data, we are beginning to understand the diversity of coronavirus through exploring the origin and evolution of SARS-CoV-2 from a scientific point of view.
Figure-2 Animal origins of human coronaviruses (HCoVs)
(Jie Cui et al., 2019）
Professor Shi of Wuhan Institute of Virology published an article in Nature Review - "Origin and evolution of pathogenic coronaviruses", which explains the origin and evolution of coronaviruses and discusses the reasons why SARS and MERS coronaviruses are both pathogenic and deadly. This article emphasizes the diversity of bat coronaviruses and the possibility of cross-species transmission, as well as the relationship of coronavirus phylogeny from an evolutionary perspective. This study outlined the context of SARS coronavirus cross-species transmission to humans. Dramatically, this article was published in March 2019 – well before the outbreak of COVID-19. The classification of coronaviruses and the analysis of the sequence diversity of various coronaviruses described in this article has provided a good theoretical basis for the investigation of SARS-CoV-2 that began at the end of 2019.
As cross-species viral transmission is not a simple endeavor, the key to discovering potential reservoir species depend on analyzing sequencing data from the variety of coronaviruses seen among species. Since bats live in caves to hibernate throughout the winter, if viruses were transferred cross species, there must be one or more intermediate hosts to have initiated the spread in late 2019. The presence of viruses in different species is not the same, as shown by the sequence diversity (see figure-3) for similar coronaviruses.
Figure-3 The sequence diversity of coronaviruses
(Jie Cui et al., 2019)
In March 2020, the research team from the Science Institute of Beijing University published an article entitled "On the origin and continuing evolution of SARS-CoV-2" in the National Science Review. The team investigated the extent of molecular divergence between the novel coronavirus (SARS-CoV-2) and other related coronaviruses. Analyzing from the nucleotide differences in the genome, they compared each structural unit of the functional protein with a variety of similar coronaviruses, and used the molecular phylogenetic tree of coronavirus-related systems to analyze the possible variants of SARS-CoV-2 structurally. Finally, it was found that there was only a 4% variability in genomic nucleotides between the bat RaTG13 coronavirus and SARS-CoV-2.
Figure-4 Molecular divergence and selective pressures during the evolution of SARS-CoV-2 and related viruses
(Xiaolu Tang et al., 2020)
The above data describes the possible origin of SARS-CoV-2 and diversity of coronaviruses from the perspective of viral evolutionary phylogeny and viral functional molecular phylogeny. This indicates that viruses need to have their own evolutionary advantages to jump across species to humans. Since the SARS-CoV-2 Spike (S) protein confers the ability to bind to host receptors, the origin of the human transmission may be inferred from this nucleotide sequence. In figure-4, the high similarity of ribosome-binding domain (RBD) nucleotide sequence between SARS-CoV-2 and GD Pangolin-CoV is shown to exceed that of SARS-CoV-2 and Bat RaTG13 – implicating pangolins as intermediate hosts.
Further analysis revealed differences in the key positions of ribosome-binding motif (RBM) residues of viral S protein (shown in table-1) that corresponded to the infectivity of SARS-CoV-2 and SARS viruses across different species. Five important residues underwent natural selections critical for the evolutionary advantages of SARS-CoV-2, and one of the important reasons for the differing phenotypes of infection across species. Studies have shown that these five residues play a vital role in the virus recognizing the ACE2 host receptor, enabling initial viral invasion into host cells.
Table-1 Critical residue changes in the RBMs of coronaviruses (CoVs)
(Yushun Wan et al., 2020)
The power of evolution enables viruses to leap across animal species. For SARS-CoV-2 to achieve long-term survival and development, in addition to adapting itself constantly, external factors are critical in reducing the threshold for an advantageous mutation to occur. For example, successful cross-species transmission of SARS-CoV-2 may be mediated by effective vectors. In the following section, we will discuss how the ACE2 host receptor proteins differ among species, mediating infectivity of SARS-CoV-2. Additionally, we explore how SARS-CoV-2 evolved to infect humans through receptor adaptation.
From the initial SARS outbreak through 2015, National Institutes of Health (NIH) of the US conducted a study on the phenotypes of different animal models infected with SARS virus. This study uncovered varied infection phenotypes across species, as some were susceptible to illness, while others were not. According to the results, virus-infected inbred mouse models prepared were not susceptible to serious illness. Syrian hamster model was tested for infection with different strains of SARS coronavirus, and it was found that FrK-1 strain infection can cause limited death in hamsters. In addition, the ferret model shows symptoms that are similar to humans infected by SARS viruses, while non-primate mammals such as African green monkeys, cynomolgus macaques, and rhesus monkeys have not exhibited fatality as a sequelae. These phenomena were later found by researchers and scientists in SARS-CoV-2 studies as well. Therefore, the phenotypes of animals infected with SARS-CoV-2 are different from the those seen in humans with COVID-19. The infection variability was found to mainly be caused by the species differences between ACE2 - the main receptor of SARS-CoV-2 among species.
It is known that the ACE2 protein is the main host receptor of SARS and SARS-CoV-2, and conformational changes or amino acid differences of ACE2 will influence its ability to bind with the virus. The team of the Department of Veterinary and Biomedical Sciences of University of Minnesota jointly published a review "Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus". Through their data analysis, it was found that there are changes in the virus-contacting residues of ACE2 from different host species (see table-2).
Table-2 Comparison of critical residues of ACE2 in different host
(Yushun Wan et al., 2020)
Variation in key ACE2 residues can lead to conformational changes that result in differing ability to bind to the virus, which helps explain the divergent characteristics of SARS-CoV-2 infection across various species.
We have limited knowledge about the characteristics of SARS-CoV-2 in different species, but there are several genetic similarities to zoonotic viruses, particularly among bats and pangolins. Amino acid mutations and sequence recombination occurring throughout the virus’ evolution have made the structure of the virus more advanced, enabling it to make the leap across species. The variation of the ACE2 receptor between species leads to differences in the infectivity, affinity, pathogenicity, and lethality of the viruses among different animals.
Analyzing the differences between similar viruses across species allows us to better understand the evolutionary process and progression of the virus. This approach has led to the consensus that SARS-CoV-2 transmission likely spread from bats to humans, with a potential intermediary host. All genetics studies thus far have ruled out the possibility that SARS-CoV-2 was lab-made. Viruses are constantly searching for a suitable host to ensure survival - by adapting itself to a variety of complex body environments, this virus finally discovered an opportunity for survival in humans. As a parasitic entity, the purpose of the virus is not to kill humans, but to obtain the best way to survive with living creatures and maintain opportunities for infection. As we can now understand the theoretical nature of coronaviruses, we can do more to help control the current pandemic and prevent the emergence of new viruses in the future. Society can learn practical measures to take from an enhanced awareness of pathogens, following scientific recommendations to take strict preventive measures, enhance physical fitness, develop treatments and vaccines, and more.
Understanding the ins and outs of SARS-CoV-2 is of vital importance to instituting a good prevention system to continue the high-quality survival of human beings. Whether for COVID-19 or a new infectious disease/virus that may appear in the future, it is best to prepare in advance for the emergence of a novel contagion. The application of model animals is particularly important, since they can be used to simulate the symptoms of virus infection in humans, providing data for the development of vaccines and antiviral drugs, which is critical in protecting public health during an outbreak.
In the next review, we will focus on the phenotypes appearing in mice of different strains upon infection with SARS-CoV-2, as well as the advantages of the ACE2 mouse models developed by Cyagen.