Early neutralizing IgG response to Chikungunya virus in infected patients targets a dominant linear epitope on the E2 glycoprotein.
Bottom Line: E2EP3 is located at the N-terminus of the E2 glycoprotein and prominently exposed on the viral envelope.Screening of E2EP3 across different patient cohorts and in non-human primates demonstrated the value of this epitope as a good serology detection marker for CHIKV infection already at an early stage.Mice vaccinated by E2EP3 peptides were protected against CHIKV with reduced viremia and joint inflammation, providing a pre-clinical basis for the design of effective vaccine against arthralgia-inducing CHIKV and other alphaviruses.
Affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.Show MeSH
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Mentions: The strong response against the first two peptides suggested that the epitope (termed here ‘E2EP3’) should be present within the overlapping part of peptides P1-1 and P1-2. The sequence alignment revealed that the overlap (STKDNFNVYKATRPYLAH) is located proximal to the furin cleavage site. The site is required for the proteolytic generation of E2 and E3 glycoproteins from the common precursor protein (Ozden et al, 2008) and the ‘furin loop’ is conserved in alphaviruses (Ozden et al, 2008). The availability of the recent crystal structure of the CHIKV E1–E2 glycoprotein (Voss et al, 2010) further allowed the precise localization of E2EP3 epitope. In the mature E2 glycoprotein (Fig 3A), the amino acids of E2EP3 form the N-terminal part of the molecule. This region is prominently exposed on the surface of the virus, forming a stalk that points away from the virus envelope (Fig 3A and B). Control peptides from other regions of the E2 glycoprotein did not detect any reactivity from the patients' plasma (Supporting information Fig 2A). Using a library of peptides containing a series of alanine-substituted amino acids (Cunningham & Wells, 1989), we were able to identify both the core-binding region as well as the key amino acids recognized by anti-E2EP3 antibodies of patients' plasma. The result of the alanine-scan (Fig 4A and Supporting information Fig 3) was in good correlation with the crystal structure (Fig 4B). Based on this data, the core-binding region of E2EP3 comprises aa3-10 (STKDNFNVYK), which represents the exposed part of the sequence (aa1-3 were not resolved in the crystal structure).
Affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.