Tsinghua and other teams from the bat “poison does not invade” to find the new corona virus answer

Bats are “poisonous” natural virus reservoirs, why do they carry a large number of viruses but protect them from it? Can humans seek a universal solution to multiple viruses from here? On March 31st, Beijing time, a new study published online by the Tsinghua University Center for High-Precision Innovation in Structural Biology, Duke-National University School of Medicine, China Center for Disease Control and Prevention, the Institute of Zoology of the Chinese Academy of Sciences, and Duke University in the United States, published a new study on BioRxiv, a preprinted website. genome-wide screenings in bat cells identify MTHFD1 a target of broad antiviral therapy”.

(Original title: Tsinghua and other teams from the bat “100 poison not invasion” to find the answer: found new coronavirus inhibitors)

Journalist He Liping

The study has not yet been peer-reviewed.

By systematically screening more than 20,000 genes in bat cells, the team identified dozens of key bat genes on which virus replication depended, and found a common new host gene, MTHFD1.

Further studies have found that the level of MTHFD1 expression in bat cells is much lower than that of the corresponding tissues in humans, which may be related to physiological changes in bat adaptation to flying life.

The team eventually found that the inhibitor of the host protein MTHFD1, carolacton, effectively inhibited the replication of new coronaviruses.

They believe that the results of the research will not only help the development of new coronavirus drugs, strong fight against the epidemic, but also the future human fight against the outbreak of the foundation.

Tan Xu, a researcher at Tsinghua University’s Center for High-Precision Innovation in Structural Biology, and Professor Wang Linfa of the Duke-National University School of Medicine, are co-authors of the paper. Cui Jin, Ph.D. student at Tsinghua University’s School of Pharmacy, Ph.D., Ye Wei, Duke-Singapore National University School of Medicine Danielle Anderson, and Dr. Huang Baoying of the China Center for Disease Control and Prevention are the first authors of the thesis. The study was also supported by Dr. So Young Kim of Duke University in the United States, a researcher at the Cdc’s Tan Wenjie, a researcher at the Institute of Animals of the Chinese Academy of Sciences.

In addition, Tan Xu Lab’s work is jointly funded by Tsinghua University’s epidemic prevention and control science and technology emergency response, Beijing Structural Biology High-Precision Innovation Center, Tsinghua-North University Life Sciences Joint Center and National Nature Foundation’s Outstanding Youth Fund.

Humans need broad-spectrum antiviral drugs

From SARS to Ebola to conomepred (COVID-19) in 2019, infectious diseases caused by the virus have been one of the leading diseases that seriously endanger global health. The history of these outbreaks has given us a deep erston to realize that the most urgent task is to develop a wide spectrum of antiviral drugs.

Broad-spectrum antiviral drugs can save critically ill patients from emergency treatment of new outbreaks of viral infection, and have an inestimable effect on reducing mortality and alleviating the epidemic.

However, traditional antiviral drugs target viral proteins, which are difficult to play in dealing with the many different types of viruses that are emerging, and viruses can easily develop resistance by mutatetheir their genes.

In contrast, because multiple viruses in-cell replication requires many common host proteins to complete replication cycles, new antiviral drugs for host proteins dependent on viral replication may have the advantages of broad spectrum and resistance.

Bats are natural hosts of viruses such as Ebola virus, SARS-CoV, MERS-CoV, Henniba virus genus and neo-coronavirus, the paper said. Starting with bat genomics analysis, the team used leading functional genomics methods to systematically look for host factors that rely on virus lifecycle dependence, and to find new antiviral drug targets by understanding the molecular mechanisms of virus-host factor interactions.

Why do bats “do not invade” ?

Bats belong to the mammal’s winged hand and are the only mammals that can actually fly. Many large-scale deadly outbreaks in recent years have been linked to bats, which have been recognized as the most important natural “water reservoir” of emerging viruses.

The authors note that SARS in 2003, Ebola in 2014 and outbreaks of new coronary pneumonia in late 2019 have caused huge economic losses and psychological panic around the world. There is a lot of evidence that bats are the natural hosts of these disease-causing viruses, which spread from bats to an intermediate host that eventually led to a large-scale outbreak of the outbreak.

However, it is puzzling that while bats can carry a variety of pathogenic viruses, they do not cause obvious symptoms in bats. Bats’ high tolerance to viruses may also be an important reason why they can carry and spread multiple viruses.

Zhou Peng, a researcher at the Wuhan Virus Research Institute of the Chinese Academy of Sciences, told reporters at www.thepapr.cn that “from an immunological point of view, the bat’s immune system is still very unique, it is the only mammal that will continue to fly.” Flying this ability causes many of its genes to be different from those of humans or other mammals, many of which are related to antivirals and immune systems. “

Zhou Peng and others have previously confirmed that bats always maintain a certain amount of interferon expression. Interferon is a critical antiviral protein, and if it always remains “low” in the body, it is equivalent to the animal itself with “all-weather protection” of the defense mechanism.

“Our preliminary conclusion now is that its immune pathways will maintain a certain amount of defense, but will not be over-immunized. Viruses such as SARS can eventually die from excessive inflammatory responses, but bats’ inflammatory responses and innate immunity do not over-attack, so they will not be damaged. “

Zhou Peng and others have previously mentioned similar ideas, studying the unique nature of bats carrying viruses without disease, which is expected to allow humans to learn how to fight the virus.

The authors believe that the physiological studies of bats and the results of genome sequencing provide a variety of explanations for their ability to tolerate viruses, and that functional genomics screening can help us better understand the host factors needed to infect bat cells with viruses.

More than 20,000 genetic screenings: How is the virus infection mechanism different from that in bats and humans?

Based on the above background, the team established the first genome-wide CRISPR knockout library of bats (Black Monster Fox Manta, Pteropus alecto) and completed a genome-wide CRISPR screening of influenza virus infections in the influenza virus of black-and-water fox manta nephral cells (PaKi cells). The host factor sly lying on more than 20 virus replications was found (Figure 1).

Meanwhile, the Duke-Nuds National University School of Medicine’s Wang Linfa team used RNA interference (RNAi) to screen bat cells for mumps virus infection and found dozens of host factors for viral dependence.

By comparing the screening results of the two groups, the team found that they included important genes for intracellular swallowing and protein secretion pathways, similar to human cell infections, suggesting that viral infections in bat cells and human cells were conservatively dependent on these pathways.

In addition, both groups of screenings found a common new host gene, MTHFD1. MTHFD1 encodes methylene tetrahydrofolate dehydrogenase, an important metabolic enzyme for the synthesis of niobium base, the component of DNA and RNA.

Interestingly, none of the virus host factors previously working on whole genome screening viruses in human cells have been found. Further studies have found that the level of MTHFD1 expression in bat cells is much lower than that of the corresponding tissues in humans, which may be related to physiological changes in bat adaptation to flying life.

Overall, the team systematically screened more than 20,000 genes in bat cells and identified dozens of key bat genes on which virus replication depended. These genes are conservative in bat and human function, but differences in gene expression levels may determine the different pathological outcomes of viral infections.

Discover inhibitorcarolacton

The team further found that RNA viruses, including mumps virus, maroon virus, Zika virus, etc. are very sensitive to the absence of MTHFD1, and MTHFD1 inhibitor carolacton has a very strong inhibitor of the replication of the above virus. This phenomenon is significant in both bats and human cells.

Carolacton is a natural product that is used as an antibiotic candidate molecule to inhibit bacterial membrane production.

Happily, in collaboration with the CDC, the team found that carolacton was also effective in suppressing the replication of new coronaviruses in human cells, and that the effective concentration of antivirals was much lower than cytotoxicity, demonstrating good medicinal efficicity.

Genetic screening of bats led to the discovery of MTHFD1, a new antiviral drug target, and carolacton, a small antiviral molecule. The results also suggest that we can learn from studying the mechanisms of viral infection in bats.

The whole genome CRISPR screening of bat cells found a key host factor for RNA virus replication, MTHFD1, whose inhibitor carolacton can effectively inhibit the replication of new coronaviruses in primate cell lines.

It is reported that the research team will follow up on animal infection models to further carolacton and its derivatives of antiviral function of preclinical testing, hoping to use it as a broad-spectrum antiviral drug to the early clinical. The effects of MTHFD1-related genes on viruses and their drug targeting are also expected to provide more drug-candidate molecules.

In addition, the genome-wide screening system that the team built up earlier will play a significant role in the study of other tissue cells in bats, especially immune cells, helping researchers continue to explore more of the mysteries of bats.