Indirect Mouse Model for the Evaluation of Potential Antiviral Compounds: Results with Venezuelan Equine Encephalomyelitis Virus

Kuehne, Ralph W.; Pannier, Wallace L.; Stephen, Edward L.

doi:10.1128/aac.11.4.683

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…For our application of viral pathogenesis and antiviral efficacy analysis, in vivo modeling is more efficient than current systems 11,12 for multiple reasons. We are able to detect specific key steps for disease development, CNS invasion 1 in the case of TC83, before any clinical disease develops.…”

Section: Discussionmentioning

confidence: 99%

<em>In Vivo</em> Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

Poussard¹,

Patterson

Taylor

et al. 2012

JoVE

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Modern advancements in imaging technology encourage further development and refinement in the way viral research is accomplished. Initially proposed by Russel and Burch in Hume's 3Rs (replacement, reduction, refinement), the utilization of animal models in scientific research is under constant pressure to identify new methodologies to reduce animal usage while improving scientific accuracy and speed. A major challenge to Hume's principals however, is how to ensure the studies are statistically accurate while reducing animal disease morbidity and overall numbers. Vaccine efficacy studies currently require a large number of animals in order to be considered statistically significant and often result in high morbidity and mortality endpoints for identification of immune protection. We utilized in vivo imaging systems (IVIS) in conjunction with a firefly bioluminescent enzyme to progressively track the invasion of the central nervous system (CNS) by an encephalitic virus in a murine model. Typically, the disease progresses relatively slowly, however virus replication is rapid, especially within the CNS, and can lead to an often, lethal outcome. Following intranasal infection of the mice with TC83-Luc, an attenuated Venezuelan equine encephalitis virus strain modified to expresses a luciferase gene; we are able to visualize virus replication within the brain at least three days before the development of clinical disease symptoms. Utilizing CNS invasion as a key encephalitic disease development endpoint we are able to quickly identify therapeutic and vaccine protection against TC83-Luc infection before clinical symptoms develop. With IVIS technology we are able to demonstrate the rapid and accurate testing of drug therapeutics and vaccines while reducing animal numbers and morbidity. Video LinkThe video component of this article can be found at http://www.jove.com/video/4429/ Protocol 1. Animal Preparation 1. Animal arrival: Upon arrival to the animal biosafety level 2 (ABSL2) facilities, allow animals a minimum of 2 days to acclimate to their new environment. Following this rest period, inspect the animals to evaluate their health and overall physical appearance. 1. When utilizing fluorescent reporters it is important to place all animal subjects on an alfalfa free diet to limit the amount of GI autofluorescence and background signal.2. Shave animals: To improve the bioluminescent signal detected from the cranial region during imaging; shave the heads of all the animals. Anesthetize the animals with a mixture of oxygen gas and vaporized isoflurane. Once the animals are fully anesthetized, use electric clippers to shave their heads. Once finished with shaving, return the animals to their cages and observe for complete recovery from the effects of the anesthesia. 3. Bio Medic Data Systems (BMDS) transponder insertion (to take place following shaving of the mice while the animals are fully anesthetized):For a less invasive means to track temperature implant a preprogrammed BMDS wireless transponder subcutaneousl...

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Section: Discussionmentioning

confidence: 99%

<em>In Vivo</em> Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

Poussard¹,

Patterson

Taylor

et al. 2012

JoVE

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“…One objective of this study was to further characterize the C3H/HeN mouse model of TC-83 VEEV disease for use in antiviral experiments. TC-83 infection of out bred mouse strains has been used as an indirect model for the evaluation of antiviral compounds (Kuehne et al, 1977). Exogenous interferon has been used in the prevention or treatment of disease in mice infected with wild-type VEEV strains (Lukaszewski and Brooks, 2000).…”

Section: Introductionmentioning

confidence: 99%

C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection

et al. 2008

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The TC-83 vaccine strain of Venezuelan equine encephalitis virus (VEEV) causes encephalitis and death in C3H/HeN mice infected by intranasal (i.n.) instillation. Since TC-83 is exempt as a select agent, this mouse model was used in the evaluation of antiviral therapies. Virus titers in the brains of infected mice peaked on 4 dpi and persisted at high levels until death at 9.4+/-0.5 dpi. Mouse brains appeared histologically normal on 2 dpi, but developed meningoencephalitis, neuropil vacuolation, and gliosis by 8 dpi. Results from a protein cytokine array showed significant elevations over time in interleukin (IL)-1alpha, IL-1beta, IL-6, IL-12, MCP-1, IFNgamma, TNFalpha, MIP-1alpha, and RANTES in homogenized brain samples of infected mice. Immunohistochemical staining showed a colocalization of viral antigen with neuron markers. Treatment with interferon-alpha B/D or ampligen significantly improved survival, brain virus titer and cytokine levels, mean day-to-death, and weight change in infected mice. The time-course of infection and disease parameters of mice infected with TC-83 VEEV were similar in many ways to disease parameters in mice infected with other VEEV strains. Thus, infection of C3H/HeN mice with TC-83 VEEV may serve as a suitable model for the evaluation of antiviral compounds for the treatment of this viral disease.

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“…In mouse models, poly(ICLC) is effective against rabies virus (1) and Venezuelan equine encephalomyelitis virus (9). In therapeutic studies, efficacy is retained when treatment is initiated as late as 8 and 24 h postinfection with yellow fever (17) and Japanese encephalitis (5) viruses, respectively.…”

mentioning

confidence: 99%

Enhanced therapeutic efficacy of poly(ICLC) and ribavirin combinations against Rift Valley fever virus infection in mice

Kende

Lupton

Rill

et al. 1987

Antimicrob Agents Chemother

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Indirect Mouse Model for the Evaluation of Potential Antiviral Compounds: Results with Venezuelan Equine Encephalomyelitis Virus

Cited by 7 publications

References 24 publications

<em>In Vivo</em> Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

<em>In Vivo</em> Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection

Enhanced therapeutic efficacy of poly(ICLC) and ribavirin combinations against Rift Valley fever virus infection in mice

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