Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate
Abstract Currently, there are no commercially available live‐attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non‐structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201810092 |
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| author | Yi‐Hao Chan Teck‐Hui Teo Age Utt Jeslin JL Tan Siti Naqiah Amrun Farhana Abu Bakar Wearn‐Xin Yee Etienne Becht Cheryl Yi‐Pin Lee Bernett Lee Ravisankar Rajarethinam Evan Newell Andres Merits Guillaume Carissimo Fok‐Moon Lum Lisa FP Ng |
| author_facet | Yi‐Hao Chan Teck‐Hui Teo Age Utt Jeslin JL Tan Siti Naqiah Amrun Farhana Abu Bakar Wearn‐Xin Yee Etienne Becht Cheryl Yi‐Pin Lee Bernett Lee Ravisankar Rajarethinam Evan Newell Andres Merits Guillaume Carissimo Fok‐Moon Lum Lisa FP Ng |
| author_sort | Yi‐Hao Chan |
| collection | DOAJ |
| description | Abstract Currently, there are no commercially available live‐attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non‐structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type‐I IFN response compared to WT‐CHIKV. Adult mice infected with this nsP‐mutant exhibited a mild joint phenotype with low‐level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti‐inflammatory IL‐10 versus pro‐inflammatory IL‐1β and IL‐18 balance during CHIKV nsP‐mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP‐mutant‐infected mice with WT‐CHIKV or the closely related O'nyong‐nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection. |
| format | Article |
| id | doaj-art-7a62dbf737b044d2be9223a7852aa699 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7a62dbf737b044d2be9223a7852aa6992025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-04-0111611710.15252/emmm.201810092Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidateYi‐Hao Chan0Teck‐Hui Teo1Age Utt2Jeslin JL Tan3Siti Naqiah Amrun4Farhana Abu Bakar5Wearn‐Xin Yee6Etienne Becht7Cheryl Yi‐Pin Lee8Bernett Lee9Ravisankar Rajarethinam10Evan Newell11Andres Merits12Guillaume Carissimo13Fok‐Moon Lum14Lisa FP Ng15Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Institute of Technology, University of TartuSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Sir William Dunn School of Pathology, University of OxfordFred Hutchinson Cancer Research CenterSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology, A*STARFred Hutchinson Cancer Research CenterInstitute of Technology, University of TartuSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Abstract Currently, there are no commercially available live‐attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non‐structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type‐I IFN response compared to WT‐CHIKV. Adult mice infected with this nsP‐mutant exhibited a mild joint phenotype with low‐level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti‐inflammatory IL‐10 versus pro‐inflammatory IL‐1β and IL‐18 balance during CHIKV nsP‐mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP‐mutant‐infected mice with WT‐CHIKV or the closely related O'nyong‐nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection.https://doi.org/10.15252/emmm.201810092chikungunyalive‐attenuated vaccinemutationneutralizing antibodynon‐structural protein |
| spellingShingle | Yi‐Hao Chan Teck‐Hui Teo Age Utt Jeslin JL Tan Siti Naqiah Amrun Farhana Abu Bakar Wearn‐Xin Yee Etienne Becht Cheryl Yi‐Pin Lee Bernett Lee Ravisankar Rajarethinam Evan Newell Andres Merits Guillaume Carissimo Fok‐Moon Lum Lisa FP Ng Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate EMBO Molecular Medicine chikungunya live‐attenuated vaccine mutation neutralizing antibody non‐structural protein |
| title | Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate |
| title_full | Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate |
| title_fullStr | Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate |
| title_full_unstemmed | Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate |
| title_short | Mutating chikungunya virus non‐structural protein produces potent live‐attenuated vaccine candidate |
| title_sort | mutating chikungunya virus non structural protein produces potent live attenuated vaccine candidate |
| topic | chikungunya live‐attenuated vaccine mutation neutralizing antibody non‐structural protein |
| url | https://doi.org/10.15252/emmm.201810092 |
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