Effect of exogenous interferon and an interferon inducer on western equine encephalitis virus disease in a hamster model (original) (raw)
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Antiviral Research, 2008
The TC-83 vaccine strain of Venezuelan equine encephalitis virus (VEEV) causes encephalitis and death in C3H/HeN mice infected by intranasal 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 IL-1α, IL-1β, IL-6, IL-12, MCP-1, IFNγ, TNFα, MIP-1α, and RANTES in homogenized brain samples of infected mice. Immunohistochemical staining showed a colocalization of viral antigen with neuron markers. Treatment with interferon-α 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
Virology, 1999
To investigate the role of type I interferon (IFN) and its regulatory transacting proteins, interferon regulatory factors (IRF-1 and IRF-2), in early protection against infection with virulent Venezuelan equine encephalitis virus (VEE), we utilized mice with targeted mutations in the IFN-␣/ receptor, IRF-1, or IRF-2 genes. IFN-␣/-receptor knockout mice are highly susceptible to peripheral infection with virulent or attenuated VEE, resulting in their death within 24 and 48 h, respectively. Treatment of normal macrophages with anti-IFN-␣/ antibody prior to and during infection with molecularly cloned virulent VEE resulted in increased VEE replication. However, treatment with high doses of IFN or IFN-inducing agents failed to alter percentage mortality or average survival times in mice challenged with a low dose of virulent VEE. In IRF-1 and IRF-2 knockout mice (IRF-1 Ϫ/Ϫ and IRF-2 Ϫ/Ϫ), the 100% protection against virulent VEE that is conferred by attenuated VEE within 24 h in control C57BL/6 mice was completely absent in IRF-2 Ϫ/Ϫ mice, whereas 50% of IRF-1 Ϫ/Ϫ mice were protected. IRF-2 Ϫ/Ϫ mice were deficient in clearing VEE virus from the spleen and the brain compared to the heterozygous IRF-2 ϩ/Ϫ knockout or C57BL/6 (ϩ/ϩ) mice. Furthermore, a distinct pattern of histopathological changes was observed in brains of IRF-2 Ϫ/Ϫ mice after VEE exposure. Taken together, these findings imply that the altered immune response in IRF-1 and IRF-2 knockout mice results in altered virus dissemination, altered virus clearance, and altered virus-induced pathology. Thus, type I interferon, as well as IRF-1 and IRF-2, appears to play an important and necessary role in the pathogenesis of, and protection against, VEE infection.
Variation in Interferon Sensitivity and Induction among Strains of Eastern Equine Encephalitis Virus
Journal of Virology, 2005
America (SA) it has rarely been associated with human disease, suggesting that SA strains are less virulent. To evaluate the hypothesis that this virulence difference is due to a greater ability of NA strains to evade innate immunity, we compared replication of NA and SA strains in Vero cells pretreated with interferon (IFN). Human IFN-␣, -, and -␥ generally exhibited less effect on replication of NA than SA strains, supporting this hypothesis. In the murine model, no consistent difference in IFN induction was observed between NA and SA strains. After infection with most EEEV strains, higher viremia levels and shorter survival times were observed in mice deficient in IFN-␣/ receptors than in wild-type mice, suggesting that IFN-␣/ is important in controlling replication. In contrast, IFN-␥ receptor-deficient mice infected with NA and SA strains had similar viremia levels and mortality rates to those of wild-type mice, suggesting that IFN-␥ does not play a major role in murine protection. Mice pretreated with poly(I-C), a nonspecific IFN inducer, exhibited dose-dependent protection against fatal eastern equine encephalitis, further evidence that IFN is important in controlling disease. Overall, our in vivo results did not support the hypothesis that NA strains are more virulent in humans due to their greater ability to counteract the IFN response. However, further studies using a better model of human disease are needed to confirm the results of differential human IFN sensitivity obtained in our in vitro experiments.
Virology, 2007
Western equine encephalitis virus (WEEV) is a positive-sense, single-stranded RNA virus which is transmitted to equines and humans through mosquito bites. WEEV infects the central nervous system with severe complications and even death. There are no human vaccine and antiviral drugs. We investigated whether adenovirus-mediated expression of interferon alpha could be used for pre-and post-exposure protection against a lethal WEEV challenge in mice. A human adenoviral vector (Ad5-mIFNα) expressing mouse interferon alpha was constructed. We found that Ad5-mIFNα provided 100% protection against various WEEV strains in mice after a single intramuscular inoculation at 24 h, 48 h or 1 week before the challenge. When given as a single inoculation at 6 h after the challenge, Ad5-mIFNα delayed the progress of WEEV infection and provided about 60% protection. Our findings suggest that adenovirus-mediated expression of interferon alpha can be an alternative approach for the prevention and treatment of WEEV infection.
Journal of Virology, 2000
Venezuelan equine encephalitis virus (VEEV) is a highly infectious alphavirus endemic in parts of Central and South America. The disease is transmitted by mosquitoes, and the natural reservoir is the small rodent population, with epidemics occurring in horses and occasionally humans. Following infection, VEEV replicates in lymphoid tissues prior to invasion of the central nervous system. Treatment of VEEV-infected BALB/c mice with polyethylene glycol-conjugated alpha interferon (PEG IFN-α) results in a greatly enhanced survival from either a subcutaneous or an aerosol infection. Virus is undetectable within PEG IFN-α-treated individuals by day 30 postinfection (p.i.). Treatment results in a number of changes to the immune response characteristics normally associated with VEEV infection. Increased macrophage activation occurs in PEG IFN-α-treated BALB/c mice infected with VEEV. The rapid activation of splenic CD4, CD8, and B cells by day 2 p.i. normally associated with VEEV infection...
Eastern equine encephalitis virus
Archives of Virology, 1974
Eastern equine encephalitis (EEE) virus replication in rabbit kidney (I~K) cells was inhibited by interferon (IF). Interferon protected against the virus-induced shutoff of host protein synthesis and partially suppressed the synthesis of EEE structural proteins in infected cells. High doses (300-3000 units) inhibited the labeling of viral I~NA in interferon-treated RK cells by as much as 98 per cent, as measured by TCA precipitation following 10, 30 or 60 minute labeling period. Sucrose gradient analysis confirmed that incorporation of 3H-uridine into 23S and 40S viral RNA was inhibited by interferon, the latter being slightly more sensitive. The logarithm of the surviving fraction of each virus-specific event persisting in the interferon-treated infected cell was a linear function of the logarithm of the IF dose over a 1000-fold concentration range. The relative interferon sensitivities of the viral events measured were from highest to lowest : EEE yield > EEE I~NA synthesis > EEE-induced CPE > EEE-indueed shutoff of RK cell protein synthesis-~ EEE structural protein synthesis.
Vaccine, 2007
Western equine encephalitis virus (WEEV) causes a fatal infection of the central nervous system in humans and horses. However, neither human vaccine nor antiviral drug is available. We found previously that immunization of mice with two doses of an adenovirus-vectored WEEV vaccine, Ad5-WEEV, confers complete protection against homologous WEEV challenge. In this paper, we report that a single-dose injection of Ad5-WEEV completely protected mice against both homologous and heterologous strains of WEEV at 1 week after immunization. In addition, mice immunized with Ad5-WEEV were protected when challenged at 13 weeks after a single-dose immunization. Therefore, the protection conferred by Ad5-WEEV is rapid, cross-protective, and long-lasting. These results warrant further development of Ad5-WEEV into an emergency vaccine that can be used during a natural outbreak or a bioterrorism attack.
Virology Journal, 2015
Background: Eastern equine encephalitis virus (EEEV), an arbovirus, is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae. EEEV is considered the most deadly of the mosquito-borne alphaviruses due to the high case fatality rate associated with clinical infections, reaching up to 75 % in humans and 90 % in horses. In patients that survive acute infection, neurologic sequelae are often devastating. Although natural infections are acquired by mosquito bite, EEEV is also highly infectious by aerosol. This fact, along with the relative ease of production and stability of this virus, has led it to being identified as a potential agent of bioterrorism. Methods: To characterize the clinical course and outcome of EEEV strain FL93-939 infection, we compared clinical parameters, cytokine expression, viremia, and viral titers in numerous tissues of mice exposed by various routes. Twelve-week-old female BALB/c mice were infected by the intranasal, aerosol, or subcutaneous route. Mice were monitored for clinical signs of disease and euthanized at specified time points (6 hpi through 8 dpi). Blood and tissues were harvested for cytokine analysis and/or viral titer determination. Results: Although all groups of animals exhibited similar clinical signs after inoculation, the onset and severity differed. The majority of those animals exposed by the aerosol route developed severe clinical signs by 4 dpi. Significant differences were also observed in the viral titers of target tissues, with virus being detected in the brain at 6 hpi in the aerosol study. Conclusion: The clinical course and outcome of EEEV infection in mice is dependent on route of exposure. Aerosol exposure to EEEV results in acute onset of clinical signs, rapid neuroinvasion, and 100 % mortality.
Virulence variation among isolates of western equine encephalitis virus in an outbred mouse model
Journal of General Virology, 2009
Little is known about viral determinants of virulence associated with western equine encephalitis virus (WEEV). Here, we have analysed six North American WEEV isolates in an outbred CD1 mouse model. Full genome sequence analyses showed ¡2.7 % divergence among the six WEEV isolates. However, the percentage mortality and mean time to death (MTD) varied significantly when mice received subcutaneous injections of 10 3 p.f.u. of each virus. Two WEEV strains, McMillan (McM) and Imperial 181 (IMP), were the most divergent of the six in genome sequence; McM caused 100 % mortality by 5 days post-infection, whereas IMP caused no mortality. McM had significantly higher titres in the brain than IMP. Similar differences in virulence were observed when McM and IMP were administered by aerosol, intranasal or intravenous routes. McM was 100 % lethal with an MTD of 1.9 days when 10 3 p.f.u. of each virus was administered by intracerebral inoculation; in contrast, IMP caused no mortality. The presence of IMP in the brains after infection by different routes and the lack of observed mortality confirmed that IMP is neuroinvasive but not neurovirulent. Based on morbidity, mortality, MTD, severity of brain lesions, virus distribution patterns, routes of infection and differences in infection of cultured cells, McM and IMP were identified as high-and low-virulence isolates, respectively.