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GARDNER, Christina L, Jozef HRITZ, Chengqun SUN, Dana L. VANLANDINGHAM, Timothy Y. SONG, Elodie GHEDIN, Stephen HIGGS, William B. KLIMSTRA and Kate D. RYMAN. Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design. PLOS Neglected Tropical Diseases. San Francisco: PUBLIC LIBRARY SCIENCE, 2014, vol. 8, No 2, p. "nestránkováno", 16 pp. ISSN 1935-2735. doi:10.1371/journal.pntd.0002719.
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Basic information
Original name Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design
Authors GARDNER, Christina L (840 United States of America), Jozef HRITZ (703 Slovakia, guarantor, belonging to the institution), Chengqun SUN (840 United States of America), Dana L. VANLANDINGHAM (840 United States of America), Timothy Y. SONG (840 United States of America), Elodie GHEDIN (840 United States of America), Stephen HIGGS (840 United States of America), William B. KLIMSTRA (840 United States of America) and Kate D. RYMAN (840 United States of America).
Edition PLOS Neglected Tropical Diseases, San Francisco, PUBLIC LIBRARY SCIENCE, 2014, 1935-2735.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30000 3. Medical and Health Sciences
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 4.446
RIV identification code RIV/00216224:14740/14:00075086
Organization unit Central European Institute of Technology
Doi http://dx.doi.org/10.1371/journal.pntd.0002719
UT WoS 000332017500001
Keywords in English EQUINE ENCEPHALITIS-VIRUS; INDIAN-OCEAN OUTBREAK; SINDBIS VIRUS; CELL-CULTURE; YELLOW-FEVER; MOUSE MODEL; E2 GLYCOPROTEIN; NEONATAL MICE; BINDING; ATTACHMENT
Tags kontrola MP, ok, rivok
Tags International impact, Reviewed
Changed by Changed by: Martina Prášilová, učo 342282. Changed: 17. 10. 2014 12:44.
Abstract
Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash and severe persistent polyarthralgia in humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine candidates is of critical importance. Historically, live-attenuated vaccines (LAVs) for protection against arthropod-borne viruses have been created by blind cell culture passage leading to attenuation of disease, while maintaining immunogenicity. Attenuation may occur via multiple mechanisms. However, all examined arbovirus LAVs have in common the acquisition of positively charged amino acid substitutions in cell-surface attachment proteins that render virus infection partially dependent upon heparan sulfate (HS), a ubiquitously expressed sulfated polysaccharide, and appear to attenuate by retarding dissemination of virus particles in vivo. We previously reported that, like other wild-type Old World alphaviruses, CHIKV strain, La Réunion, (CHIKV-LR), does not depend upon HS for infectivity. To deliberately identify CHIKV attachment protein mutations that could be combined with other attenuating processes in a LAV candidate, we passaged CHIKV-LR on evolutionarily divergent cell-types. A panel of single amino acid substitutions was identified in the E2 glycoprotein of passaged virus populations that were predicted to increase electrostatic potential. Each of these substitutions was made in the CHIKV-LR cDNA clone and comparisons of the mutant viruses revealed surface exposure of the mutated residue on the spike and sensitivity to competition with the HS analog, heparin, to be primary correlates of attenuation in vivo. Furthermore, we have identified a mutation at E2 position 79 as a promising candidate for inclusion in a CHIKV LAV.
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