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. 2006 Mar 28;103(13):4994-9.
doi: 10.1073/pnas.0509961103. Epub 2006 Mar 20.

Venezuelan encephalitis emergence mediated by a phylogenetically predicted viral mutation

Michael Anishchenko  1 , Richard A Bowen, Slobodan Paessler, Laura Austgen, Ivorlyne P Greene, Scott C Weaver
Affiliations

Venezuelan encephalitis emergence mediated by a phylogenetically predicted viral mutation

Michael Anishchenko et al. Proc Natl Acad Sci U S A. .

Abstract

RNA viruses are notorious for their genetic plasticity and propensity to exploit new host-range opportunities, which can lead to the emergence of human disease epidemics such as severe acute respiratory syndrome, AIDS, dengue, and influenza. However, the mechanisms of host-range change involved in most of these viral emergences, particularly the genetic mechanisms of adaptation to new hosts, remain poorly understood. We studied the emergence of Venezuelan equine encephalitis virus (VEEV), an alphavirus pathogen of people and equines that has had severe health and economic effects in the Americas since the early 20th century. Between epidemics, VEE disappears for periods up to decades, and the viral source of outbreaks has remained enigmatic. Combined with phylogenetic analyses to predict mutations associated with a 1992-1993 epidemic, we used reverse genetic studies to identify an envelope glycoprotein gene mutation that mediated emergence. This mutation allowed an enzootic, equine-avirulent VEEV strain, which circulates among rodents in nearby forests to adapt for equine amplification. RNA viruses including alphaviruses exhibit high mutation frequencies. Therefore, ecological and epidemiological factors probably constrain the frequency of VEE epidemics more than the generation, via mutation, of amplification-competent (high equine viremia) virus strains. These results underscore the ability of RNA viruses to alter their host range, virulence, and epidemic potential via minor genetic changes. VEE also demonstrates the unpredictable risks to human health of anthropogenic changes such as the introduction of equines and humans into habitats that harbor zoonotic RNA viruses.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Phylogenetic tree of representatives of all VEE complex alphaviruses and all serotypes of VEEV generated by using the neighbor-joining program implemented in paup* 4.0 software. Homologous sequences of eastern equine encephalitis virus, the sister to the VEE complex, were used as an outgroup. Bayesian and maximum parsimony analyses produced trees with identical topologies except for the order of divergence of Pixuna and Cabassou viruses. Virus strains are designated by virus name (subtype in the VEE complex in parentheses) or VEEV serotype, followed by abbreviated country and year of isolation and strain name. Enzootic strains isolated from mosquitoes, humans, or sentinel animals infected in sylvatic habitats are gray; epidemic strains isolated from mosquitoes, humans, or horses during major VEE epidemics are black. Numbers indicate neighbor-joining bootstrap values for groups to the right. Branches are colored to minimize phenotypic changes, and transitions from gray to black indicate hypothetical phenotypic changes from enzootic to epidemic leading to VEE outbreaks. Maximum parsimony analyses were used to assign each amino acid substitution to each branch in the tree, and the box shows the two substitutions in the E2 envelope glycoprotein represented in the branch with the predicted enzootic-to-epidemic transition in 1992.
Fig. 2.
Fig. 2.
Mean viremia titers expressed in suckling mouse intracranial lethal dose 50% units for four horses infected s.c. with 2,000 plaque-forming units of VEEV rescued from the enzootic infectious clone (ZPC738), as well four horses infected with mutants with Arg residues at E2 positions 193 and 213, and five horses infected with a double-mutant containing both Arg residues. Bars indicate SEM.
Fig. 3.
Fig. 3.
Histopathological analyses of brain samples from animals infected with VEEV strains, as described in Materials and Methods, showing representative lesions. (A) Strain ZPC738 containing the Arg residue at E2 position 193, day 7 postinfection. Congestion and vascular and perivascular (Virchow–Robin space) infiltration by mononuclear cells (arrows) in the brainstem. (B) Strain ZPC738 containing the Arg residue at E2 position 213, day 7 postinfection. Congestion and vascular and perivascular (Virchow–Robin space) infiltration by mononuclear cells (arrows) in the brainstem; Inset shows higher magnification of an area of extensive infiltration. (C) Strain ZPC738 containing the Arg residues at E2 positions 193 and 213, day 7 postinfection. Congestion and vascular and perivascular (Virchow–Robin space) infiltration by mononuclear cells (vertical arrows), as well as neuronal cell death characterized by angulation of hypereosinophilic neurons and microhemorrhage (horizontal arrows) in the brainstem.
Fig. 4.
Fig. 4.
Cartoon showing the emergence process for epidemic VEEV strains supported by this study. Enzootic, sylvatic VEEV strains in serotype ID (gray) are transmitted continuously among rodent reservoir hosts such as spiny rats (Proechimys spp.) and cotton rats (Sigmodon spp.) by mosquito vectors in the subgenus Culex (Melanoconion). Mutations in the E2 envelope glycoprotein, such as the Thr-213→Arg identified in this study, are selected by equines because they generate high-titer viremia sufficient for amplification. The resultant epidemic strains (black) in serotypes IAB and IC are transmitted by abundant floodwater mosquitoes such as Aedes and Psorophora spp., which have wide host ranges including equines and humans. Spillover to humans who live in proximity to infected equines results in epidemics involving up to hundreds of thousands of people before equine mortality and immunity exhaust the supply of amplification hosts or vector populations decline.
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Comment in

  • The evolution of viral emergence.
    Holmes EC. Holmes EC. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4803-4. doi: 10.1073/pnas.0601166103. Epub 2006 Mar 27. Proc Natl Acad Sci U S A. 2006. PMID: 16567658 Free PMC article. No abstract available.

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References

    1. Guan Y., Zheng B. J., He Y. Q., Liu X. L., Zhuang Z. X., Cheung C. L., Luo S. W., Li P. H., Zhang L. J., Guan Y. J., et al. Science. 2003;302:276–278. - PubMed
    1. Rota P. A., Oberste M. S., Monroe S. S., Nix W. A., Campagnoli R., Icenogle J. P., Penaranda S., Bankamp B., Maher K., Chen M. H., et al. Science. 2003;300:1394–1399. - PubMed
    1. Nichol S. T., Spiropoulou C. F., Morzunov S., Rollin P. E., Ksiazek T. G., Feldman H., Sanchez A., Childs J., Zaki S., Peters C. J. Science. 1993;262:914–917. - PubMed
    1. Feldmann H., Wahl-Jensen V., Jones S. M., Stroher U. Trends Microbiol. 2004;12:433–437. - PubMed
    1. Gao F., Bailes E., Robertson D. L., Chen Y., Rodenburg C. M., Michael S. F., Cummins L. B., Arthur L. O., Peeters M., Shaw G. M., et al. Nature. 1999;397:436–441. - PubMed

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