Venezuelan equine encephalitis emergence: Enhanced vector infection from a single amino acid substitution in the envelope glycoprotein

Abstract

In 1993 and 1996, subtype IE Venezuelan equine encephalitis (VEE) virus caused epizootics in the Mexican states of Chiapas and Oaxaca. Previously, only subtype IAB and IC VEE virus strains had been associated with major outbreaks of equine and human disease. The IAB and IC epizootics are believed to emerge via adaptation of enzootic (sylvatic, equine-avirulent) strains for high titer equine viremia that results in efficient infection of mosquito vectors. However, experimental equine infections with subtype IE equine isolates from the Mexican outbreaks demonstrated neurovirulence but little viremia, inconsistent with typical VEE emergence mechanisms. Therefore, we hypothesized that changes in the mosquito vector host range might have contributed to the Mexican emergence. To test this hypothesis, we evaluated the susceptibility of the most abundant mosquito in the deforested Pacific coastal locations of the VEE outbreaks and a proven epizootic vector, Ochlerotatus taeniorhynchus. The Mexican epizootic equine isolates exhibited significantly greater infectivity compared with closely related enzootic strains, supporting the hypothesis that adaptation to an efficient epizootic vector contributed to disease emergence. Reverse genetic studies implicated a Ser 3 Asn substitution in the E2 envelope glycoprotein as the major determinant of the increased vector infectivity phenotype. Our findings underscore the capacity of RNA viruses to alter their vector host range through minor genetic changes, resulting in the potential for disease emergence.

Eilat virus, a unique alphavirus with host range restricted to insects by RNA replication

“…Available data suggest that mutations in the CSEs or glycoproteins can alter host range (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). However, these mutations result in change in fitness in vertebrate or insect host but do not completely abolish replication.…”

Venezuelan encephalitis emergence mediated by a phylogenetically predicted viral mutation

“…This finding suggests that ecological factors including transport of nascent epidemic strains to locations conducive to equine amplification, as well as epidemiologic and ecologic factors including equine herd immunity and mosquito densities, constrain the frequency of VEE epidemics rather than the generation of amplification-competent mutants. Envelope glycoprotein mutations that facilitate transmission by Aedes (Ochlerotatus) taeniorhynchus, an important mosquito vector, could also be involved in some epidemics (45,46). However, there is no evidence of enhanced vector infection by the 1992-1993 IC strains compared with the putative ID progenitors, such as strain ZPC738 (47).…”

Experimental Infection of Potential Reservoir Hosts with Venezuelan Equine Encephalitis Virus, Mexico

“…This strain had been isolated in 2001 from a sentinel hamster in coastal Chiapas, Mexico, and passaged once in Vero cells to generate a suffi cient volume of high-titer virus for experimentation. We chose this strain because it is the most recent low-passage isolate of VEEV from the outbreak area and because transmission of this strain by VEEV mosquito vector species from this area has been studied (14,15). Additionally, this strain is genetically highly similar to the equine-virulent strains that were isolated during the 1993 outbreak (11) and caused encephalitis in horses (R. Bowen, pers.…”