FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
PloS one2013; 8(3); e60427; doi: 10.1371/journal.pone.0060427

Molecular determinants of mouse neurovirulence and mosquito infection for Western equine encephalitis virus.

Abstract: Western equine encephalitis virus (WEEV) is a naturally occurring recombinant virus derived from ancestral Sindbis and Eastern equine encephalitis viruses. We previously showed that infection by WEEV isolates McMillan (McM) and IMP-181 (IMP) results in high (∼90-100%) and low (0%) mortality, respectively, in outbred CD-1 mice when virus is delivered by either subcutaneous or aerosol routes. However, relatively little is known about specific virulence determinants of WEEV. We previously observed that IMP infected Culex tarsalis mosquitoes at a high rate (app. 80%) following ingestion of an infected bloodmeal but these mosquitoes were infected by McM at a much lower rate (10%). To understand the viral role in these phenotypic differences, we characterized the pathogenic phenotypes of McM/IMP chimeras. Chimeras encoding the E2 of McM on an IMP backbone (or the reciprocal) had the most significant effect on infection phenotypes in mice or mosquitoes. Furthermore, exchanging the arginine, present on IMP E2 glycoprotein at position 214, for the glutamine present at the same position on McM, ablated mouse mortality. Curiously, the reciprocal exchange did not confer mouse virulence to the IMP virus. Mosquito infectivity was also determined and significantly, one of the important loci was the same as the mouse virulence determinant identified above. Replacing either IMP E2 amino acid 181 or 214 with the corresponding McM amino acid lowered mosquito infection rates to McM-like levels. As with the mouse neurovirulence, reciprocal exchange of amino acids did not confer mosquito infectivity. The identification of WEEV E2 amino acid 214 as necessary for both IMP mosquito infectivity and McM mouse virulence indicates that they are mutually exclusive phenotypes and suggests an explanation for the lack of human or equine WEE cases even in the presence of active transmission.
Get Full Text
Publication Date: 2013-03-27 PubMed ID: 23544138PubMed Central: PMC3609757DOI: 10.1371/journal.pone.0060427Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study investigates the molecular factors that determine the neurovirulence (ability to infect the nervous system) of the Western equine encephalitis virus (WEEV) in mice and its infection potential in mosquitoes. The study reveals the viral attributes responsible for the varying degrees to which different strains of WEEV can infect mice and mosquitoes. Specifically, it identifies a particular amino acid in the WEEV E2 protein that, when replaced, can influence both mosquito infectivity and mouse virulence.

Background

  • The Western equine encephalitis virus is a recombinant virus, which is a product of combination of parts from different viruses, in this case, the Sindbis and Eastern equine encephalitis viruses.
  • The study was motivated by the observation that two isolates of WEEV, McMillan (McM) and IMP-181 (IMP), had drastically different effects when used to infect mice: McM resulted in extremely high mortality rates, while IMP had virtually no effect. Similarly, IMP successfully infected mosquitoes at a high rate, whereas McM had a noticeably lesser effect.

Aims and Objectives

  • The research was designed to understand the viral factors that could explain these significant differences.
  • The researchers used chimeras of McM and IMP to understand their pathogenic phenotypes. Chimeras refer to organisms (in this case, viruses) that are made up of cells from two different lines.

Results

  • The study found that chimeras which carried the E2 protein of McM on an IMP backbone demonstrated the most significant change in infection phenotypes in both mice and mosquitoes.
  • Specifically, substituting the amino acid arginine (found on the IMP E2 glycoprotein at position 214) with glutamine (found at the same position in McM) eliminated mouse mortality. However, the inverse substitution didn’t make the IMP virus virulent in mice.
  • It was also observed that the same E2 protein site at 214 amino acid, which was found to affect mouse neurovirulence, also had influence over mosquito infectivity. When either amino acid position 181 or 214 in IMP was replaced with the equivalent McM amino acid, mosquito infection rates decreased to the level caused by the McM strain.

Conclusions

  • The identification of this mutual amino acid site that influences both mouse virulence and mosquito infectivity of different WEEV strains implies that these traits are mutually exclusive.
  • This finding might explain why there are limited cases of Western equine encephalitis in humans or horses, even in areas with active mosquito transmission.

Cite This Article

APA
Mossel EC, Ledermann JP, Phillips AT, Borland EM, Powers AM, Olson KE. (2013). Molecular determinants of mouse neurovirulence and mosquito infection for Western equine encephalitis virus. PLoS One, 8(3), e60427. https://doi.org/10.1371/journal.pone.0060427

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 8
Issue: 3
Pages: e60427
PII: e60427

Researcher Affiliations

Mossel, Eric C
  • Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Ledermann, Jeremy P
    Phillips, Aaron T
      Borland, Erin M
        Powers, Ann M
          Olson, Ken E

            MeSH Terms

            • Amino Acid Sequence
            • Amino Acids / metabolism
            • Animals
            • Chickens / virology
            • Culex / virology
            • Encephalitis Virus, Western Equine / genetics
            • Encephalitis Virus, Western Equine / growth & development
            • Encephalitis Virus, Western Equine / pathogenicity
            • Encephalomyelitis, Western Equine / genetics
            • Encephalomyelitis, Western Equine / virology
            • Humans
            • Mice
            • Molecular Sequence Data
            • Nervous System / pathology
            • Nervous System / virology
            • Point Mutation / genetics
            • Sequence Alignment
            • Subcutaneous Tissue / virology
            • Viremia
            • Virulence / genetics

            Grant Funding

            • R01 AI046435 / NIAID NIH HHS
            • U54 AI065357 / NIAID NIH HHS
            • R01 AI46435 / NIAID NIH HHS
            • U54AI-065357 / NIAID NIH HHS

            Conflict of Interest Statement

            The authors have declared that no competing interests exist.

            References

            This article includes 31 references
            1. Meyer KF, Haring CM, Howitt B. THE ETIOLOGY OF EPIZOOTIC ENCEPHALOMYELITIS OF HORSES IN THE SAN JOAQUIN VALLEY, 1930.. Science 1931 Aug 28;74(1913):227-8.
              pubmed: 17834966doi: 10.1126/science.74.1913.227google scholar: lookup
            2. Griffin DE. Alphaviruses. .
            3. Reisen WK, Monath TP. Western equine encephalomyelitis. .
            4. Reisen WK, Kramer LD, Chiles RE, Green EG, Martinez VM. Encephalitis virus persistence in California birds: preliminary studies with house finches.. J Med Entomol 2001 May;38(3):393-9.
              pubmed: 11372964doi: 10.1603/0022-2585-38.3.393google scholar: lookup
            5. . Confirmed and Probable Western Equine Encephalitis Virus Neuroinvasive Disease Cases, Human, United States, 1964–2010, By State. .
            6. Emmons RW, Grodhaus G, Bayer EV. Serveillance for arthropod borne viruses and disease by the California State Departament of Health, 1974. Proc Calif Mosq Cont Assoc 43: 59–65.
            7. Forrester NL, Kenney JL, Deardorff E, Wang E, Weaver SC. Western Equine Encephalitis submergence: lack of evidence for a decline in virus virulence.. Virology 2008 Oct 25;380(2):170-2.
              pmc: PMC2574696pubmed: 18801549doi: 10.1016/j.virol.2008.08.012google scholar: lookup
            8. Reisen WK, Fang Y, Brault AC. Limited interdecadal variation in mosquito (Diptera: Culicidae) and avian host competence for Western equine encephalomyelitis virus (Togaviridae: Alphavirus).. Am J Trop Med Hyg 2008 Apr;78(4):681-6.
              pubmed: 18385369
            9. Zhang M, Fang Y, Brault AC, Reisen WK. Variation in western equine encephalomyelitis viral strain growth in mammalian, avian, and mosquito cells fails to explain temporal changes in enzootic and epidemic activity in California.. Vector Borne Zoonotic Dis 2011 Mar;11(3):269-75.
              pmc: PMC3063703pubmed: 21395409doi: 10.1089/vbz.2010.0078google scholar: lookup
            10. Logue CH, Bosio CF, Welte T, Keene KM, Ledermann JP, Phillips A, Sheahan BJ, Pierro DJ, Marlenee N, Brault AC, Bosio CM, Singh AJ, Powers AM, Olson KE. Virulence variation among isolates of western equine encephalitis virus in an outbred mouse model.. J Gen Virol 2009 Aug;90(Pt 8):1848-1858.
              pmc: PMC2887574pubmed: 19403754doi: 10.1099/vir.0.008656-0google scholar: lookup
            11. Bianchi TI, Aviles G, Monath TP, Sabattini MS. Western equine encephalomyelitis: virulence markers and their epidemiologic significance.. Am J Trop Med Hyg 1993 Sep;49(3):322-8.
              pubmed: 8103970doi: 10.4269/ajtmh.1993.49.322google scholar: lookup
            12. Blakqori G, Weber F. Efficient cDNA-based rescue of La Crosse bunyaviruses expressing or lacking the nonstructural protein NSs.. J Virol 2005 Aug;79(16):10420-8.
              pmc: PMC1182624pubmed: 16051834doi: 10.1128/jvi.79.16.10420-10428.2005google scholar: lookup
            13. Saxton-Shaw KD, Ledermann JP, Borland EM, Stovall JL, Mossel EC, Singh AJ, Wilusz J, Powers AM. O'nyong nyong virus molecular determinants of unique vector specificity reside in non-structural protein 3.. PLoS Negl Trop Dis 2013;7(1):e1931.
              pmc: PMC3554527pubmed: 23359824doi: 10.1371/journal.pntd.0001931google scholar: lookup
            14. Hardy JL, Presser SB, Chiles RE, Reeves WC. Mouse and baby chicken virulence of enzootic strains of western equine encephalomyelitis virus from California.. Am J Trop Med Hyg 1997 Aug;57(2):240-4.
              pubmed: 9288823doi: 10.4269/ajtmh.1997.57.240google scholar: lookup
            15. Tsetsarkin KA, Weaver SC. Sequential adaptive mutations enhance efficient vector switching by Chikungunya virus and its epidemic emergence.. PLoS Pathog 2011 Dec;7(12):e1002412.
              pmc: PMC3234230pubmed: 22174678doi: 10.1371/journal.ppat.1002412google scholar: lookup
            16. Atasheva S, Krendelchtchikova V, Liopo A, Frolova E, Frolov I. Interplay of acute and persistent infections caused by Venezuelan equine encephalitis virus encoding mutated capsid protein.. J Virol 2010 Oct;84(19):10004-15.
              pmc: PMC2937817pubmed: 20668087doi: 10.1128/jvi.01151-10google scholar: lookup
            17. Jupille HJ, Oko L, Stoermer KA, Heise MT, Mahalingam S, Gunn BM, Morrison TE. Mutations in nsP1 and PE2 are critical determinants of Ross River virus-induced musculoskeletal inflammatory disease in a mouse model.. Virology 2011 Feb 5;410(1):216-27.
              pmc: PMC3017666pubmed: 21131014doi: 10.1016/j.virol.2010.11.012google scholar: lookup
            18. Strauss EG, Stec DS, Schmaljohn AL, Strauss JH. Identification of antigenically important domains in the glycoproteins of Sindbis virus by analysis of antibody escape variants.. J Virol 1991 Sep;65(9):4654-64.
              pmc: PMC248920pubmed: 1714515doi: 10.1128/jvi.65.9.4654-4664.1991google scholar: lookup
            19. Meyer WJ, Johnston RE. Structural rearrangement of infecting Sindbis virions at the cell surface: mapping of newly accessible epitopes.. J Virol 1993 Sep;67(9):5117-25.
              pmc: PMC237909pubmed: 7688818doi: 10.1128/jvi.67.9.5117-5125.1993google scholar: lookup
            20. Li L, Jose J, Xiang Y, Kuhn RJ, Rossmann MG. Structural changes of envelope proteins during alphavirus fusion.. Nature 2010 Dec 2;468(7324):705-8.
              pmc: PMC3057476pubmed: 21124457doi: 10.1038/nature09546google scholar: lookup
            21. Mukhopadhyay S, Zhang W, Gabler S, Chipman PR, Strauss EG, Strauss JH, Baker TS, Kuhn RJ, Rossmann MG. Mapping the structure and function of the E1 and E2 glycoproteins in alphaviruses.. Structure 2006 Jan;14(1):63-73.
              pmc: PMC2757649pubmed: 16407066doi: 10.1016/j.str.2005.07.025google scholar: lookup
            22. Pierro DJ, Powers EL, Olson KE. Genetic determinants of Sindbis virus strain TR339 affecting midgut infection in the mosquito Aedes aegypti.. J Gen Virol 2007 May;88(Pt 5):1545-1554.
              pubmed: 17412985doi: 10.1099/vir.0.82577-0google scholar: lookup
            23. Pierro DJ, Powers EL, Olson KE. Genetic determinants of Sindbis virus mosquito infection are associated with a highly conserved alphavirus and flavivirus envelope sequence.. J Virol 2008 Mar;82(6):2966-74.
              pmc: PMC2258978pubmed: 18160430doi: 10.1128/jvi.02060-07google scholar: lookup
            24. Lustig S, Jackson AC, Hahn CS, Griffin DE, Strauss EG, Strauss JH. Molecular basis of Sindbis virus neurovirulence in mice.. J Virol 1988 Jul;62(7):2329-36.
              pmc: PMC253389pubmed: 2836615doi: 10.1128/jvi.62.7.2329-2336.1988google scholar: lookup
            25. Lee P, Knight R, Smit JM, Wilschut J, Griffin DE. A single mutation in the E2 glycoprotein important for neurovirulence influences binding of sindbis virus to neuroblastoma cells.. J Virol 2002 Jun;76(12):6302-10.
              pmc: PMC136218pubmed: 12021363doi: 10.1128/jvi.76.12.6302-631-.2002google scholar: lookup
            26. Tsetsarkin KA, McGee CE, Volk SM, Vanlandingham DL, Weaver SC, Higgs S. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. aegypti mosquitoes.. PLoS One 2009 Aug 31;4(8):e6835.
              pmc: PMC2729410pubmed: 19718263doi: 10.1371/journal.pone.0006835google scholar: lookup
            27. Woodward TM, Miller BR, Beaty BJ, Trent DW, Roehrig JT. A single amino acid change in the E2 glycoprotein of Venezuelan equine encephalitis virus affects replication and dissemination in Aedes aegypti mosquitoes.. J Gen Virol 1991 Oct;72 ( Pt 10):2431-5.
              pubmed: 1919525doi: 10.1099/0022-1317-72-10-2431google scholar: lookup
            28. Brault AC, Powers AM, Ortiz D, Estrada-Franco JG, Navarro-Lopez R, Weaver SC. Venezuelan equine encephalitis emergence: enhanced vector infection from a single amino acid substitution in the envelope glycoprotein.. Proc Natl Acad Sci U S A 2004 Aug 3;101(31):11344-9.
              pmc: PMC509205pubmed: 15277679doi: 10.1073/pnas.0402905101google scholar: lookup
            29. Zhang R, Hryc CF, Cong Y, Liu X, Jakana J, Gorchakov R, Baker ML, Weaver SC, Chiu W. 4.4 Å cryo-EM structure of an enveloped alphavirus Venezuelan equine encephalitis virus.. EMBO J 2011 Aug 9;30(18):3854-63.
              pmc: PMC3173789pubmed: 21829169doi: 10.1038/emboj.2011.261google scholar: lookup
            30. Voss JE, Vaney MC, Duquerroy S, Vonrhein C, Girard-Blanc C, Crublet E, Thompson A, Bricogne G, Rey FA. Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography.. Nature 2010 Dec 2;468(7324):709-12.
              pubmed: 21124458doi: 10.1038/nature09555google scholar: lookup
            31. Nagata LP, Hu WG, Parker M, Chau D, Rayner GA, Schmaltz FL, Wong JP. Infectivity variation and genetic diversity among strains of Western equine encephalitis virus.. J Gen Virol 2006 Aug;87(Pt 8):2353-2361.
              pubmed: 16847131doi: 10.1099/vir.0.81815-0google scholar: lookup

            Citations

            This article has been cited 24 times.
            Subscribe to our newsletter
            Join 99,780 horse owners like you who receive our email updates on horse health and nutrition.