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

Abstract

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.

Encephalitic Development in Alphaviral Infection

“…C3H/HeN and BALB/C mice vaccinated dermally with TC-83, the live attenuated vaccine strain, survive. However, aerosol or IN infection with TC83 results in 90-100% mortality in C3H/HeN animals unlike inbred counterparts BALB/C that respond with no evidence of mortality (Julander, et al, 2007;Julander, et al, 2008c;Steele, et al, 2007;Steele, et al, 1998;Steele, et al, 2006). Similar experiences have shown that route of administration can alter neuroinvasion with nonpathogenic viruses failing to enter the CNS by peripheral routes, but exhibiting the ability to enter the CNS by IC, IN, or aerosol administration.…”

“…Direct invasion of the brain via the bloodstream does not seem to be significant in VEE infection. Neuroinvasion results in caudal spread of the virus, and ultimately, overwhelming disseminated brain infection (Julander, et al, 2007;Julander, et al, 2008b). Thus, all routes of infection in mice with virulent forms of the virus result in neuroinvasion.…”

“…Animals genetically modified with deficiencies in type I IFN signaling are highly susceptible to VEE infection and, even attenuated strains are uniformly lethal in these animals (White, et al, 2001). Additionally, artificial induction of type I IFN or prophylactic administration of type I IFN delays or prevents death in animal models (Julander, et al, 2008b). In the case of IN or aerosol infection, the rapid entry of virus to the CNS results in earlier neuroinvasion and may limit or alter the effectiveness of early innate immune mechanisms such as IFN or other as yet other unexplored mechanisms.…”

Mouse models of alphavirus-induced inflammatory disease

“…Like most strains, the clinical features of disease in these mice include lethargy, hunched posture and weight loss. This commonly used model also exhibits a similar CNS disease to that seen in other animal models, such as the development of meningo-encephalitis, gliosis and multifocal neurophil vacuolation (Julander et al, 2008). Differences do exist, however.…”

“…Breakthrough infections were more frequent with the highly virulent serogroup 1A/B viruses following aerosol challenge (Phillpotts & Wright, 1999). C3H/HeN mice are particularly sensitive to VEEV TC-83 infection when receiving the virus intranasally, intracranially or by aerosol exposure Julander et al, 2008;Ludwig et al, 2001). Like most strains, the clinical features of disease in these mice include lethargy, hunched posture and weight loss.…”