July 13, 2024

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PLOS Pathogens Review: Coronavirus “Trans-Complementation” System

PLOS Pathogens Review: Coronavirus “Trans-Complementation” System

PLOS Pathogens Review: Coronavirus “Trans-Complementation” System.  Recently, Professor Connor G. G. Bamford from Queen’s University of Belfast, UK, published a commentary on “PLOS Pathogens” and expressed his views on the “trans complementation” system of the new coronavirus. The full text is now translated as follows for readers.

PLOS Pathogens Review: Coronavirus "Trans-Complementation" System

In a study recently published in “PLOS Pathogens” [1], researchers found a safer way to find antiviral drugs against the new coronavirus SARS-CoV-2. The team led by Tsinghua University Ding Qiang used molecular virology methods to create a structure-decomposed virus-like system through “trans complementation”, allowing scientists to work in the restricted environment of a biosafety level 3 (BSL3) laboratory.

Operate SARS-CoV-2 outside. Using this research system, researchers from six scientific research institutions in China collaborated and discovered five effective antiviral drugs and studied the biology of the new coronavirus. This paper is a representative of the increasing cooperation in the scientific field during the COVID-19 pandemic, and this is what should be actively encouraged.

Since the end of 2019, the COVID-19 virus has spread globally, causing at least 100 million infections, nearly 3 million deaths, and countless patients suffering from long-term diseases (as of March 2021). What followed was economic and social chaos that had not been seen in decades. In addition, we are still in its shadow. Although the vaccine looks promising, the future is difficult to predict.

In the absence of high-efficiency immunity, drug intervention can help prevent disease deterioration and even death. Although researchers are committed to studying the biology of the coronavirus and developing targeted antiviral drugs, such as Remdesivir, the reality is cruel, because most patients are already in the advanced stage of the disease when they enter the hospital. The clinical efficacy of the drug is very limited.

Therefore, we urgently need to find new anti-coronavirus drugs to reduce the burden on the global health care system. Of course, this exploration of new therapies is best accomplished by diverse and professional scientific collaborations around the world. Using an innovative screening platform, a huge compound library of approved and unapproved drugs, to maximize the discovery of effective and safe antiviral drugs. However, due to the nature of the new coronavirus pathogen, the “fully contagious” SARS-CoV-2 virus must be operated in the BSL3 laboratory, which hinders drug screening.

The research on molecular virology in the past 50 years has allowed scientists to better control the virus, thereby avoiding the challenge posed by SARS-CoV-2. The research team led by Ding Qiang is trying to overcome this challenge. They have invented a new tool called SARS-CoV-2 trVLPs, which are virus-like particles with transcription and replication capabilities for use outside the BSL3 laboratory. Screen SARS-CoV-2 antiviral drugs (Figure 1). The system can be used to study the complete infection cycle of SARS-CoV-2 from entry, replication, transcription, translation to virus particle assembly and release.

The principle of this system is based on the fact that the N protein is essential for virus replication and packaging because it positively regulates translation, replication and assembly. Construct a full-length cDNA clone of SARS-CoV-2, delete its N gene, and replace it with the green fluorescent protein GFP reporter gene to monitor virus infection. Providing N protein “trans” in stable cell lines can package N gene-deficient viruses. Since the N gene cannot be integrated back into the viral genome, the infection is limited to a single round, but this is sufficient to find antiviral drug molecules.

PLOS Pathogens Review: Coronavirus "Trans-Complementation" System
Figure 1. The use of virus reverse genetics and “trans complementation” system to package SARS-CoV-2 virus with single-round replication capability.

As the safety of SARS-CoV-2 is very important, in order to reduce the possibility of N gene recombination into the viral genome, the research team used protein splicing technology to effectively split N into two independent genes. Although considered unlikely, the only risk may be that these modified viruses may undergo recombination and restore infectivity when they are co-infected with wild-type viruses, or that N-like genes may appear in vitro under huge selective pressure ( It has been found in the E gene deleted coronavirus [2]) to promote the recovery of multiple rounds of infection.

Through this system, the Beijing research team has identified several effective antiviral drugs in vitro. In addition, by recombining with different N genes, the research team also identified the functions of specific viral N proteins, such as the N incompatibility between SARS-CoV-2 and MERS-CoV, and the key role of amino acids at specific positions in the N protein in promoting infection. , And protein-protein interactions between N and host cytokines, rediscovered some of the interactions previously identified in animal coronaviruses [3].

Trans-complementation is an important technology in molecular virology to study basic biology and genetics. The system published on “PLOS Pathogens” is not the only system available for SARS-CoV-2. Recently, Shi Peiyong’s team from the University of Texas Medical Branch reported a similar system [4]. Unlike the Beijing Ding Qiang team, the American Shi Peiyong team removed two genes: “ORF3” and “E”, and then provided it in the form of “trans complementation”. Shi Peiyong’s team carefully studied the safety of this system and found that this single-round infection virus is not pathogenic in rodents. In the past, the Luis Enjuanes laboratory has also published similar systems for other coronaviruses to study MERS-CoV[5] and transmissible gastroenteritis coronavirus TGEV[6]. In addition, as a wonderful tool for scientific discovery, single-cycle viruses can also be used to develop safer vaccines, such as Ebola vaccine [7].

If the experimental system and program are indeed fully shared, efforts like Ding Qiang’s team have highlighted the necessity and potential of the democratization of science in the face of major social challenges. There are many such examples in the scientific community, such as the construction and sharing of the SARS-CoV-2 pseudovirus in Benhur Lee’s laboratory [8], and the construction of the COVID-19 system at the Virus Research Center of the MRC University of Glasgow [9]. It is hoped that such efforts will increase the efficiency of scientific research without endangering the safety of researchers and their communities. Enhanced sharing may have an impact during the COVID-19 pandemic, but it may have a greater impact on the future global event handling model, such as the “next pandemic” or slow crises such as antibiotic resistance. For our own benefit, every effort should be made to encourage this behavior.


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