动物实验,埃博拉 z-bo 2020-08-19 563

　　Researchers of Ebola virus are facing major problems. Conventional laboratory mice are killed by the virus without hemorrhagic fever and other typical human symptoms. The lack of mouse disease models has severely hindered Ebola pathology and immunology research. Affected the development of drugs for this disease. Angela Rasmussen and Michael Katze of the University of Washington, and the National Institutes of Health (NIH) Toshimura tested the host response induced by 47 strains of Ebola virus in mice. Studies have shown that viral infection has different effects on different mouse strains. The latest research, published in the journal Science, laid the foundation for revealing the genetic differences behind Ebola virus susceptibility.

　　This study “confirms a problem that many people have noticed,” commented David Threadgill, a geneticist at Texas A&M University. "Before, we lost a lot of biological information because we only used one mouse strain in our research."

　　Threadgill, the first to propose the construction of collaborative crossover (CC) mice. Is one of them. CC contains hundreds of mouse strains with different genotypes. These strains were derived from 8 original strains of 5 experimental species and 3 inbred strains of wild mice. CC mice can embody the genetic variation of different mouse subspecies, and their SNP is four times higher than that of conventional laboratory mice. Although the CC mouse strain has been used in many disease studies, Katze et al. also studied the genetic differences that affect the severity of influenza in these mice.

　　In this study, researchers infected 47 CC mouse strains with a mouse version of Ebola virus. All mice showed weight loss in the early stage of infection, of which 19% were resistant to the virus and could regain body weight within 2 weeks, and 11% of the mice were partially resistant to the virus. 70% of mice after infection have a mortality rate of more than 50%. The symptoms shown in different mouse strains are also very different. Some mice only show liver inflammation, while others show signs of Ebola virus, such as abnormal blood clotting. These mice mimic the various pathological processes of human patients very well. Studies have shown that the severity of Ebola hemorrhagic fever is closely related to the genetic background of the host and cannot be explained by the virus alone. The researchers also analyzed two mouse strains with extremely high resistance and extremely high sensitivity. Vulnerable mice will develop coagulopathy, internal bleeding, splenomegaly and severe liver damage after infection. Mice infected with Ebola virus died after 5 or 6 days. Highly resistant mice lost 15% of their body weight during the first 5 days of infection, but no other symptoms. These mice recovered after 14 days. Studies have shown that the levels of viral RNA in the liver and spleen of susceptible and resistant mice are similar. However, susceptible mice produce 10 times more infectious virus than resistant mice. This suggests that mouse resistance may be related to the post-transcriptional program that inhibits the virus. In addition, the distribution of Ebola hemorrhagic fever in the livers of the two mice and the effect of the virus on blood clotting are also very different. The researchers also compared the gene expression patterns of the two mice. Studies have shown that the transcription levels of endothelial cell tyrosine kinase genes Tie1 and Tek are significantly different, and these two enzymes are involved in blood coagulation. In the eight original CC germlines, Tie1 alleles are very different, which may be related to different symptoms of mice.

　　Asmussen, Katze and others have begun to analyze gene expression data in experiments. Rasmussen said: "I want to find the characteristic genes that have a decisive influence on the outcome of infectious diseases." "This discovery will help people predict the diagnosis and prognosis of Ebola in the future."

　　Ebola researchers have been facing a big problem. Traditional laboratory mice will be killed by this virus without hemorrhagic fever and other typical human symptoms. The lack of mouse disease models has severely hindered Ebola pathology and immunology research, and also affected the development of drugs for this disease.

　　Angela Rasmussen and Michael Katze of the University of Washington, and Atsushi Okumura of NIH tested the Ebola-induced host response in 47 mouse strains. Studies have shown that viral infections have different effects on different mouse strains. This latest study, published in the journal Science, laid the foundation for revealing the genetic differences behind Ebola susceptibility.

　　This study "confirms a problem that many people have just realized," commented David Threadgill, a geneticist at Texas A&M University. "Before, people only used a single mouse strain for research, which would miss a lot of biological information."

　　Threadgill was one of the first researchers who proposed the construction of Collaborative Cross (CC) mice. CC includes hundreds of mouse lines with different genotypes, which come from eight original strains: five laboratory breeds and three inbred lines derived from wild mice. CC mice can embody the genetic variation of different mouse subspecies, and their SNPs are four times that of traditional laboratory mice.

　　The

　　CC mouse line has been used in many disease studies. Katze et al. also studied the genetic differences that affect the severity of influenza in these mice.

　　In this study, the researchers infected 47 CC mouse strains with the mouse version of Ebola virus. All mice showed weight loss at the initial stage of infection, 19% were able to resist the virus and regain weight within two weeks, and 11% of the mice were partially resistant to the virus. 70% of mice have a mortality rate of more than 50% after infection. The symptoms shown by different mouse lines are also quite different. Some mice only show liver inflammation, and some mice also show signs of Ebola infection such as blood coagulation defects.

　　These mice mimic the different pathological processes of human patients very well. Studies have shown that the severity of Ebola infection has a lot to do with the genetic background of the host, and cannot be explained from the virus alone.

　　The researchers further analyzed two mouse lines with extremely high resistance and extremely high susceptibility. Highly susceptible mice will develop coagulation defects, internal bleeding, enlarged spleen and severe liver damage after infection. Mice infected with Ebola will die after five or six days. Highly resistant mice lose 15% of their body weight in the first five days of infection, but they show no other symptoms, and these mice will recover after 14 days.

　　Studies have shown that in the liver and spleen of highly susceptible and highly resistant mice, the level of viral RNA is similar. But the infectious virus produced by susceptible mice is ten times that of resistant mice. This indicates that the mouse resistance may be related to the post-transcriptional program that inhibits the virus. In addition, the distribution of Ebola in the liver of these two mice and the effect of the virus on blood coagulation are also quite different.

　　The researchers also compared the gene expression patterns of the two mice. Studies have shown that the transcription levels of endothelial cell tyrosine kinase genes Tie1 and Tek are significantly different, and these two enzymes are related to blood coagulation. Tie1 alleles vary greatly in the eight original CC germlines, which may be the cause of the difference in symptoms in mice.

　　Rasmussen, Katze and other talents just started to analyze the gene expression data in the experiment. "We hope to find the signature genes that have a decisive influence on the outcome of the infection," Rasmussen said. "This type of discovery will help people diagnose and predict prognosis of Ebola infection in the future."