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.
journal_name
PLoS Negl Trop Disjournal_title
PLoS neglected tropical diseasesauthors
Gardner CL,Hritz J,Sun C,Vanlandingham DL,Song TY,Ghedin E,Higgs S,Klimstra WB,Ryman KDdoi
10.1371/journal.pntd.0002719subject
Has Abstractpub_date
2014-02-20 00:00:00pages
e2719issue
2eissn
1935-2727issn
1935-2735pii
PNTD-D-13-01670journal_volume
8pub_type
杂志文章abstract::Trypanosoma cruzi, the etiological agent of Chagas disease, consumes glucose and amino acids depending on the environmental availability of each nutrient during its complex life cycle. For example, amino acids are the major energy and carbon sources in the intracellular stages of the T. cruzi parasite, but their consu...
journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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abstract::Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their d...
journal_title:PLoS neglected tropical diseases
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abstract::Yellow fever virus (YFV) is a mosquito-borne flavivirus that is a major public health problem in tropical areas of Africa and South America. There have been detailed studies on YFV ecology in West Africa and South America, but current understanding of YFV circulation on the African continent is incomplete. This inadeq...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,评审
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更新日期:2013-01-01 00:00:00
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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