Venezuelan equine encephalitis (VEE) is an emerging arboviral disease and a public and veterinary health threat throughout the Americas, including the United States. Recent outbreaks in South America and Mexico underscore the continued threat of VEE emergence. VEE virus epitomizes the ability of RNA viruses to mutate and alter their host range and disease patterns, and represents ideal model systems for the study of RNA- and arboviral disease emergence. The seminal question in 60 years of VEE research has been the source of the strains responsible for major human and equine outbreaks. Our epidemiological and genetic studies indicate that epizootic, subtype LkB and IC epizootic viruses evolve from enzootic, subtype ID viruses that circulate continuously in Venezuela and Colombia. Reverse genetic studies indicate that small numbers of mutations can generate subtype IC strains from ID progenitors, and implicate positively charged E2 envelope glycoprotein amino acid changes in emergence of a 1992-93 outbreak. Field studies have identified the critical hosts of the progenitor enzootic transmission cycles, and satellite imagery has been developed to predict over a broad geographical range the locations where enzootic viruses circulate. Epidemiological and genetic data also suggest that epizootic viruses persist following the cessation of outbreaks, raising the possibility of VEE emergence without the need for mutation. All of these emergence scenarios have profound public health implications. Using a unique combination of infectious cDNA clone technology, experimental infections, and field studies, the proposed research will answer critical, remaining questions regarding VEE emergence: 1) do similar changes in the E2 glycoprotein explain the emergence of previous LkB and IC epizootic viruses; 2) are other genotypes of enzootic VEE viruses capable of mutating to become epizootic, or does the genetic backbone of the enzootic progenitor limit its ability to become equine virulent? 3) How are epizootic viruses, generated via mutation of enzootic strains in sylvatic habitats, transported to locations where ecological conditions permit the initiation of outbreaks? And, 4) do epizootic strains persist in continuous cycles following the cessation of outbreaks? Our results will advance understanding of VEE emergence mechanisms, and will predict locations of potential emergence in Latin America and Florida. This information will be invaluable in targeting prevention and control resources, especially for obtaining maximum benefit in developing countries with limited resources.
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