Can Cystic Fibrosis Treatment Improve Thanks To a Ferret?

A major breakthrough in the understanding of respiratory diseases entitled “The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease” was published on Nature Biotechnology by Dr. Xinxia Peng at the University of Washington in Seattle and Federica Di Palma and Jessica Alfoldi at the Broad Institute of MIT and Harvard. This was a collaborative research effort that enabled the researchers to discover the draft sequence of the domestic ferret (Mustela putorius euro) genome, an important animal model for multiple human respiratory diseases and considered the ‘gold standard’ for modeling human influenza virus infection and transmission, since ferrets and humans are infected by the same strains. Moreover the researchers characterized the ferret host response to two influenza virus infections as well as to cystic fibrosis by transcriptomic (RNA) analyses. This project was funded by The National Institute of Allergy and infectious Diseases, of the National Institutes of Health.

“The sequencing of the ferret genome is a big deal,” said Michael Katze, UW professor of microbiology who led the research effort, in the press release. “Every time you sequence a genome, it allows you to answer a wide range of questions you couldn’t before. Having the genome changes a field forever.”

As part of this study, the research team at Broad Institute of MIT and Harvard led by Drs. Di Palma and Alfoldi performed a gene sequence of a sable ferret, Mustela putorius euro. Then, they collaborated with Dr. Katze’s group for the transcriptome analysis that enabled the identification of all of the RNA molecules that are produced by the body or are transcribed from different regions of the genome at a specific time. This approach allowed to assess the cellular responses of the ferret when its system is infected by the influenza virus or in a disease like cystic fibrosis.

“By creating a high quality genome and transcriptome resource for the ferret, we have demonstrated how studies in non-conventional model organisms can facilitate essential bioscience research underpinning health,” said Federica Di Palma.

Yoshihiro Kawaoka’s University of Wisconsin-Madison lab performed the infection of the ferret with influenza viruses. The research team infected the ferrets with a reconstructed “Spanish flu” that killed 25 million people worldwide in 1918. They also used the swine-flu virus that caused the global pandemic of 2009-2010, and continues  to cause disease to this day. The researchers collected trachea and lung samples from the ferrets during different days after infection, day 1, 3 and 8, for transcriptome analysis. The study revealed that the two viruses affected the ferret tracheas and lungs differently. In the case of the Spanish flu, the virus induced an obvious transcriptional response in the trachea on the first day of infection and stayed constant until day 8 of infection. While for the swine-flu, the virus induced a slow-starting response that gradually grew, reaching its maximum on the 8th day of infection.

“The 1918 flu elicited a huge response on day one and that response was sustained,” said Xinxia Peng from the Katze lab, who specializes in computational biology and served as lead author of the study. “The 2009 pandemic flu triggered a response that gradually grew over several days. They had very different trajectories,” added Dr. Peng.

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Moreover, the researchers observed that the gene transcription for both viruses was quite similar but different for the trachea tissue. “This side by side comparison reveals that the host response to these two viruses differs primarily in the trachea and may explain the course of infection,” said Dr. Peng.

For the cystic fibrosis studies, John Engelhardt’s research team at the University of Iowa created a genetically engineered ferret that lacked the gene for the membrane protein called the cystic fibrosis transmembrane conductance regulator (CFTR), since mutations in this gene are responsible for this inherited disease that affects 30,000 Americans. The use of gene knockout models is a widely established approach for studying the relevance of a gene or the inheritance of a defective gene in cell function. Then, the researchers induced the cystic fibrosis condition in the gene knock-out ferrets and performed an analysis of the transcriptome, discovering that changes in the expression of genes could be observed since the first day of life and increased significantly on the following 15 days.

“We found that there are transcriptional changes from day one, right out-of-the-gate, and many of the changes are very similar to those seen in humans,” said Dr. Peng. “The findings suggest that some of the disease processes responsible for the lung damage seen in cystic fibrosis begin very early in life.”

Dr. Katze concluded that transcriptome responses seen in the influenza and in cystic fibrosis studies were very similar to the ones observed in humans. And, notably,  this study strengthens the importance of the ferret model for a better understanding of these two diseases and most probably for other type of diseases like heart disorders and diabetes.