Dissecting the role of E2 protein domains in alphavirus pathogenicity

James Weger-Lucarelli, Matthew T. Aliota, Nathan Wlodarchak, Attapon Kamlangdee, Ryan Swanson, Jorge E. Osorio

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Alphaviruses represent a diverse set of arboviruses, many of which are important pathogens. Chikungunya virus (CHIKV), an arthritis-inducing alphavirus, is the cause of a massive ongoing outbreak in the Caribbean and South America. In contrast to CHIKV, other related alphaviruses, such as Venezuelan equine encephalitis virus (VEEV) and Semliki Forest virus (SFV), can cause encephalitic disease. E2, the receptor binding protein, has been implicated as a determinant in cell tropism, host range, pathogenicity, and immunogenicity. Previous reports also have demonstrated that E2 contains residues important for host range expansions and monoclonal antibody binding; however, little is known about what role each protein domain (e.g., A, B, and C) of E2 plays on these factors. Therefore, we constructed chimeric cDNA clones between CHIKV and VEEV or SFV to probe the effect of each domain on pathogenicity in vitro and in vivo. CHIKV chimeras containing each of the domains of the E2 (ΔDomA, ΔDomB, and ΔDomC) from SFV, but not VEEV, were successfully rescued. Interestingly, while all chimeric viruses were attenuated compared to CHIKV in mice, ΔDomB virus showed similar rates of infection and dissemination in Aedes aegypti mosquitoes, suggesting differing roles for the E2 protein in different hosts. In contrast to CHIKV; ΔDomB, and to a lesser extent ΔDomA, caused neuron degeneration and demyelination in mice infected intracranially, suggesting a shift toward a phenotype similar to SFV. Thus, chimeric CHIKV/SFV provide insights on the role the alphavirus E2 protein plays on pathogenesis.

Original languageEnglish (US)
Pages (from-to)2418-2433
Number of pages16
JournalJournal of virology
Volume90
Issue number5
DOIs
StatePublished - 2016
Externally publishedYes

Bibliographical note

Funding Information:
HHS | National Institutes of Health (NIH) provided funding to Jorge E. Osorio, James David Weger-Lucarelli, Matthew T. Aliota, Nathan Wlodarchak, Attapon Kamlangdee, and Ryan Swanson under grant number AI093491-01.

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