Genetic and phenotypic studies with eastern equine encephalitis virus and its implication for the lack of human EEEV disease in South America.

摘要

In order to understand the lack of human Eastern equine encephalitis disease in South America (SA), this study investigated human exposure to the virus in Peru. Analysis of human samples revealed a low seroprevalence of EEEV antibodies in a human population living in close proximity to areas of EEEV-enzootic activity, with no evidence of previous neurological disease in these individuals with EEEV neutralizing antibodies. Febrile illness surveillance conducted in Peru revealed that 3 of 159 febrile patients presented specific EEEV-IgM antibodies, suggesting a possible association between EEEV and human illness in the population of Iquitos, Peru. The role of heterologous alphavirus cross protection against severe EEE disease was investigated experimentally and the results demonstrated that prior infection with VEEV and MAYV, the most prevalent alphaviruses in the human population in Iquitos, Peru, protected animals against fatal EEE. This study suggested that humans previously exposed to an alphavirus might not develop neurological EEEV disease.; To investigate if potential differences in sensitivity of EEEV South American (SA) and North American (NA) strains to the antiviral activity of Type I and II interferon (IFN) could account for the difference in human virulence, Vero cells were treated with human IFN-alpha, beta and gamma and the levels of reduction of virus replication determined. The results revealed that NA strains were in general resistant to the antiviral effect of Type I and II IFN whereas SA strains, in most cases, were highly sensitive to IFN. In mice, no significant difference in IFN induction was observed between NA and SA strains suggesting that IFN induction does not correlate with human virulence.; The use of reverse genetic approaches demonstrated that both the structural and nonstructural genes are important viral determinants of EEEV neurovirulence in mice. Chimeric viruses harboring the structural and nonstructural genes of an attenuated and virulent EEEV strains were equally able to cause fatal neurological disease in the animals. This finding is of great importance for the development of a live-attenuated EEEV vaccine.