Variation in Interferon Sensitivity and Induction among Strains of Eastern Equine Encephalitis Virus

Abstract

Eastern equine encephalitis virus (EEEV) causes human encephalitis in North America (NA), but in South 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.

Chimeric Sindbis/eastern equine encephalitis vaccine candidates are highly attenuated and immunogenic in mice

“…None of the adult or subadult mice we infected exhibited any signs of neurologic disease, febrile responses, or growth delays as indicated by weight gain. Although the SINV parent virus used to make the chimeras is not pathogenic in adult mice, most strains of EEEV kill 70-100% of mice infected SC, IP, IN or IC [9,32]. Our data with the highly stringent baby mouse IC model indicate that both chimeric SIN/EEEV vaccines are more attenuated than most wild-type EEEV (although the SA BeAr436087 strain is an exception to this pattern).…”

“…Chimeric alphavirus infectious cDNA clones were derived SINV strain AR339 [26], and EEEV strain FL93-939 (NA), a 1993 Florida mosquito isolate passed once in Vero cells, or BeAr436087 (SA), a 1985 Brazilian mosquito isolate passed once in C6/36 mosquito cells and once in newborn mice [9]. The nonstructural protein genes as well as the cis-acting RNA elements were derived from SINV, and the structural protein genes were derived from EEEV.…”

Capsid Protein of Eastern Equine Encephalitis Virus Inhibits Host Cell Gene Expression

“…In contrast, the flaviviruses Japanese encephalitis virus and Langat virus use the NS5 protein to block IFN signaling, suggesting that viruses from the same family that cause different spectra of human disease may use different mechanisms to overcome the IFN response (7,44,45). Studies with alphaviruses have demonstrated the importance of the IFN system in controlling infection and disease (1,22,30,60,71,73). Mice with a defect in the IFN-␣/␤ response succumb faster to infections with several alphaviruses than do wild-type mice (30,60,73).…”

Common Marmosets (Callithrix jacchus) as a Nonhuman Primate Model To Assess the Virulence of Eastern Equine Encephalitis Virus Strains

“…In contrast, human infections with NA strains can result in severe disease with neurologic complications. The cause of the apparent difference in human virulence remains unknown; however, a recent study suggests that it may be associated with viral sensitivity to interferons (1).…”