We’ve previously covered the importance of diagnostics in disease control and treatment. This is vital to controlling disease progression and transmission, but epidemiology studies can’t always show how a disease progresses or transmits. This is where scientists need a well-characterized animal model to study microbial mechanisms of pathogenesis.
One can’t simply inject a microbe into a mouse and call that an animal model. A useful animal model is one that closely mimics the course of disease seen in people. With that in mind, new research now available in the Journal of Virology describes a new ferret model of disease for the filovirus, Bundibugyo virus.
The Bundibugyo Ebola virus, first described in 2008, is a close relative of the Zaire Ebola virus, the species responsible for the 2014 West African outbreak. Like Zaire Ebola virus, Bundibugyo virus also causes hemorrhagic fever, but unlike Zaire Ebola virus, there isn’t a good animal model of Bundibugyo virus infection. Filoviruses aren’t lethal to rodents, so many animal models of filovirus (including Ebola animal models) have adapted the virus to rodent hosts through serial passaging. This serial passaging takes time, and there’s no guarantee a host-adapted virus will have the same pathology that it does in people.
Robert Kozak, working with a team of scientists led by Xiangguo Qiu, reasoned that ferrets might be superior to mice when looking for a model of filovirus study. The Filoviridae family belongs to the Mononegavirales order, which is composed of negative ssRNA viruses and also includes the Orthomyxoviridae family. Orthomyxoviridae is composed of several viral genera, including Influenza virus A, which also utilizes a ferret model (as do other Mononegavirales members). This rationale led the team to hypothesize that ferrets might be useful for filovirus study without the need for host adaptation.
When testing Bundibugyo virus infection in ferrets, all animals became sick and succumbed to their infection, supporting the researchers’ hypothesis (see graph, left). RNA viruses are notoriously mutagenic, but viral sequencing showed a majority of the same RNA sequences were present throughout the course of infection – so the ferrets were susceptible to the same viral isolates that sicken people. Less than 10% of the viral sequences had mutations, but these were largely concentrated in the viral glycoprotein that interacts with host cells, so this may be an important discovery for follow-up experiments. Importantly, many of the same hallmarks of filovirus hemorrhagic fever in humans, such as disruption of normal coagulation and decreased immune cell numbers, were also seen in the sick ferrets.
After observing a course of disease in ferrets quite similar to humans using Bundibugyo virus, the researchers tested infection with the Zaire Ebola virus. This led to similar susceptibility and symptomology as the Bundibugyo virus-infected animals, both of which mimic human infection. These results are similar to a report from an independent scientific team, also describing ferrets as a model for a number of important filoviruses, and improve on the previous mouse-adapted Zaire Ebola virus models, or immunodeficient mice used to test wild-type isolates.
A reliable, robust animal model is imperative to the study of disease progression, but also plays an important role in developing therapeutics and vaccines. Although nonhuman primates have been useful in Ebola virus studies, there are many ethical and cost-associated issues that accompany this type of model. The current report of a practical ferret model for wild-type viral isolates will undoubtedly lead to new discoveries and applications to fight this dreadful disease.
-- Julie Wolf