The evolutionary source of Wuhan’s new coronavirus has been cracked

On January 21, 2020, Researcher Yu Pei of the Pasteur Institute in Shanghai, Chinese Academy of Sciences, Zhong Wu, Researcher of the National Center for Emergency Prevention and Control drug Engineering and Technology Research of the Institute of Military Medicine, and Li Xuan, Researcher of the Key Laboratory of Synthetic Biology of the Center of Molecular Plant Excellence of the Chinese Academy of Sciences, in collaboration with Li Xuan, Science CHINA Life Sciences (Chinese Science: Life Sciences, English), published online with the title “Evolution of the novel coronavirus from the on-Wuhanin outbreak and modeling of its spike protein for risk of human transmission” paper.

The evolutionary source of Wuhan's new coronavirus has been cracked

This paper analyzes the evolutionary origin of the new coronavirus that caused the recent outbreak of pneumonia in Wuhan, and the genetic relationship with the SARS coronavirus and MERS coronavirus that caused the SARS outbreak in Guangdong in 2002. Through the structural simulation of the new coronavirus spike-protein in Wuhan, the molecular action pathway of Wuhan’s new coronavirus spike-and-human ACE2 protein and mediates the infection of humans was revealed. The results assess the potential human-to-human transmission of the new coronavirus in Wuhan, and provide a scientific theoretical basis for identifying the source and transmission route as soon as possible and formulating an efficient prevention and control strategy.

Since December 2019, an outbreak of unexplained pneumonia has occurred in Wuhan, Hubei Province. Epidemiological investigations have found that these cases of pneumonia are related to the “South China Seafood Market” in Wuhan. Wuhan City organized multidisciplinary expert consultation and investigation, using experimental testing and other means to identify the outbreak of pneumonia in Wuhan area as viral pneumonia. On January 8, 2020, a new type of coronavirus was initially identified as the pathogen of the outbreak.

The outbreak of viral pneumonia in Wuhan, which has many similarities to the outbreak of SARS in Guangdong in 2002, occurs in winter and initially occurs in live animal contact with people and animal markets, and is caused by unknown coronavirus pathogens. As of 18:00 on January 20, a total of 224 cases of pneumonia with new coronavirus infection have been reported in China, of which 217 cases have been confirmed (198 in Wuhan, 5 in Beijing and 14 in Guangdong Province); 1 case in Shandong Province). Japan reported 1 confirmed case, Thailand reported 2 confirmed cases and South Korea reported 1 confirmed case. Among the infected patients were 14 health care workers, the new coronavirus appears human-to-human and has a tendency to spread.

On January 10, 2020, the first genome sequence data of Wuhan’s new coronavirus was published, and several genome sequences of new coronaviruses isolated from patients were released. These new coronavirus genome data provide first-hand data for the study and analysis of the evolutionary origin and pathogenic pathology mechanism of the new coronavirus in Wuhan.

In order to understand the relationship between Wuhan’s new coronavirus and two coronaviruses known to be clearly infected, the researchers of this paper compared the whole genome of the new coronavirus in Wuhan with the 2002 SARS SARS coronavirus and MERS coronavirus, and found that the average was 70% and 40% of the sequence similarity. Among them, there is greater difference between the key spike genes (coded S-protein) of different coronaviruses and host cells.

The evolutionary source of Wuhan's new coronavirus has been cracked

In order to analyze the evolutionary origin and possible natural host of the new coronavirus in Wuhan, the researchers used Wuhan’s new coronavirus and collected a large amount of coronavirus data to carry out genetic evolution analysis. It was found that the new coronavirus in Wuhan belongs to the beta coronavirus genus (Betacoronavirus). Betacoronavirus is a protein-wrapped single-stranded positive-chain RNA virus that lives in and infects higher animals (including humans). In the position of the evolutionary tree, it is adjacent to the SARS (which caused the 2002 SARS) virus and the SARS-like virus, but does not belong to the SARS and SARS-like virus groups. Interestingly, their evolutionary exoplanet is a HKU9-1 coronavirus that lives in fruit bats. So the common ancestor of Wuhan coronavirus and SARS/SARS-like coronavirus is a virus similar to HKU9-1. Since the evolutionary neighbors and exoplanets of the Wuhan coronavirus have been found in all kinds of bats, it is speculated that the natural host of the Wuhan coronavirus may also be the bat. Like the SARS coronavirus that caused SARS in 2002, it is likely that unknown intermediate host vectors exist in the transmission from bat to human.

The evolutionary source of Wuhan's new coronavirus has been cracked

Because the new coronavirus in Wuhan has a great genetic distance from the SARS virus and MERS virus of 2002, the authors analyze the mechanism and pathway of Wuhan new coronavirus infection. The S-protein of SARS virus and the MERS virus S-protein are infected with respiratory epithelial cells by binding to human ACE2 protein or DPP4 protein respectively. The authors first compared the host receptor inter-processing area (RBD region) of Wuhan coronavirus and MERS virus S-protein, and found that in the RBD region, Wuhan coronavirus is similar to SARS virus, but it is very different from MERS virus, so it excludes the possibility that S-protein and DPP4 are infected with each other. However, Wuhan coronavirus S-protein and human ACE2 interoperability is also very difficult – the proven SARS virus S-protein and ACE2 each other 5 key amino acids, in Wuhan coronavirus 4 have changed.

The evolutionary source of Wuhan's new coronavirus has been cracked

In order to analyze this problem, the authors used the calculation method of molecular structure simulation to study the structural docking of The S-protein of the Coronary Virus and the human ACE2 protein, and obtained surprising results. Although 4 of the 5 key amino acids in The S-protein of Wuhan coronavirus and ACE2 protein have changed, the changed amino acids, but the overall perfect maintenance of SARS virus S-protein and ACE2 protein interaction of the original structure. Although the new structure of wuhan’s new coronavirus and ace2 protein interaction ability, due to the loss of a small number of hydrogen bonds decreased (compared to sars virus S-protein and ACE2 effect decreased), but still achieved a strong binding free energy (-50.6 kcal/mol). This result shows that The Wuhan coronavirus is an infectious mechanism of the human respiratory epithelial cell through s-protein and human ACE2. The research results predict the human infection capacity of Wuhan coronavirus, and lay a scientific theoretical foundation for scientific prevention and control, the development of prevention and control strategies and the development of detection/intervention techniques.

The evolutionary source of Wuhan's new coronavirus has been cracked

This research result is supported by the national “major new drug creation” science and technology major special project (emergency medical drug new varieties of research and development and its key innovative technology system), by the Chinese Academy of Sciences Shanghai Pasteur Institute, The National Center for Emergency Prevention and Control drug engineering and technology research of the Military Medical Research Institute and the Center for Molecular Plant Excellence of the Chinese Academy of Sciences in the synth biology key laboratory was completed. The research also received the support of the “Bioresource Seine” project of the National Natural Science Foundation of China and the Chinese Academy of Sciences’ Strategic Biological Resources Program. Xu Xinxuan, Chen Ping and Wang Jingfang are the co-authors.