小鼠模型,埃博拉 z-bo 2020-11-05 413

　　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. His pathological and immunological research 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.

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　　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 strains are also quite different. Some mice only show liver inflammation, and some mice also show signs of Ebola infection such as 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 experience 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. However, the infectious virus produced by susceptible mice is ten times that of resistant mice. This indicates that mouse resistance may be related to the post-transcriptional program that inhibits the virus. In addition, the distribution of Ebola in the liver of the 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 among 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."