Ferret models of viral pathogenesis

Enkirch, Theresa; Messling, Véronika von

doi:10.1016/j.virol.2015.03.017

Cited by 144 publications

(153 citation statements)

References 208 publications

(189 reference statements)

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“…Ferrets have also been used for many years to study viruses that affect people and are the predominant animal species for study of influenza based on wet transmission of virus and human‐similar immune response (Albrecht et al, ; Belser, Eckert, Tumpey, & Maines, ; Enkirch & von Messling, ; Kiseleva et al, ). However, susceptibility of the ferret to flaviviruses—the family of viruses that includes Zika, and also viruses that cause Dengue and Yellow fever, has yet to be concluded.…”

Section: Introductionmentioning

confidence: 99%

The effect of Zika virus infection in the ferret

Hutchinson

Chatterjee

Reyes

et al. 2019

J of Comparative Neurology

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Although initial observations of infections with the Zika virus describe a mild illness, more recent reports show that infections by Zika result in neurotropism. In 2015, substantial congenital malformations were observed, with numerous infants born with microcephaly in Brazil. To study the underlying mechanism and effects of the disease, it is critical to find suitable animal models. Rodents lack an immune system parallel to humans and also have lissencephalic brains, which are likely to react differently to infections. As the smallest gyrencephalic mammal, ferrets may provide an important animal model to study the Zika virus, as their brains share many characteristics with humans. To evaluate the prospect of using ferrets to study Zika virus infection, we injected seven pregnant jills with the PR strain subcutaneously on gestational day 21, corresponding to the initiation of corticogenesis. These injections resulted in mixed effects. Two animals died of apparent infection, and all kits were resorbed in another animal that did not die. The other four animals remained pregnant until gestational day 40, when the kits were delivered by caesarian section. We evaluated the animals using CT, MRI, diffusion tensor imaging, and immunohistochemistry. The kits displayed a number of features compatible with an infection that impacted both the brain and skull. The outcomes, however, were variable and differed within and across litters, which ranged from the absence of observable abnormalities to prominent changes, suggesting differential vulnerability of kits to infection by the Zika virus or to subsequent mechanisms of neurodevelopmental disruption.

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Section: Introductionmentioning

confidence: 99%

The effect of Zika virus infection in the ferret

Hutchinson

Chatterjee

Reyes

et al. 2019

J of Comparative Neurology

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“…Domestic ferrets (Mustela putorius furo) are used mainly for modeling respiratory diseases, such as influenza virus. While these animals require special housing/husbandry requirements and may vary in individual immunological responses and the reagents to study T-cell immunity/cytokine responses are not yet widely available (13,14), ferrets are nevertheless popular animals for studying the pathogenesis and transmission of many wild-type RNA viruses across the Mononegavirales order, including those in the Rhabdoviridae, Paramyxoviridae, Orthomyxoviridae, Togaviridae, Bunyaviridae, and Coronaviridae (15,16) families. Since Filoviridae species also belong to Mononegavirales, it is reasonable to suspect that ferrets may also be susceptible to infection by members of the Ebolavirus genus without the need for host adaptation, facilitating the capacity for studying outbreak virus strains.…”

mentioning

confidence: 99%

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

Kozak

Kroeker

et al. 2016

J Virol

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Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCEThe 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics.

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“…Ferrets have been established as an animal model for the study of several human respiratory viruses [49], including Hendra and Nipah viruses [50, 51]. Accordingly, sixteen adult ferrets were exposed to HeV via the oronasal route, monitored for clinical signs and play activity, and two or four ferrets were euthanized at 1, 2, 3, 5, 6 and 7 day post-exposure (d.p.e.).…”

Section: Resultsmentioning

confidence: 99%

Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion

et al. 2016

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Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are bat-borne viruses that cause fatal disease in humans and a range of other mammalian species. Gaining a deeper understanding of host pathways exploited by henipaviruses for infection may identify targets for new anti-viral therapies. Here we have performed genome-wide high-throughput agonist and antagonist screens at biosafety level 4 to identify host-encoded microRNAs (miRNAs) impacting henipavirus infection in human cells. Members of the miR-181 and miR-17~93 families strongly promoted Hendra virus infection. miR-181 also promoted Nipah virus infection, but did not affect infection by paramyxoviruses from other genera, indicating specificity in the virus-host interaction. Infection promotion was primarily mediated via the ability of miR-181 to significantly enhance henipavirus-induced membrane fusion. Cell signalling receptors of ephrins, namely EphA5 and EphA7, were identified as novel negative regulators of henipavirus fusion. The expression of these receptors, as well as EphB4, were suppressed by miR-181 overexpression, suggesting that simultaneous inhibition of several Ephs by the miRNA contributes to enhanced infection and fusion. Immune-responsive miR-181 levels was also up-regulated in the biofluids of ferrets and horses infected with Hendra virus, suggesting that the host innate immune response may promote henipavirus spread and exacerbate disease severity. This study is the first genome-wide screen of miRNAs influencing infection by a clinically significant mononegavirus and nominates select miRNAs as targets for future anti-viral therapy development.

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Ferret models of viral pathogenesis

Cited by 144 publications

References 208 publications

The effect of Zika virus infection in the ferret

The effect of Zika virus infection in the ferret

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion

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