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dc.contributor.authorPandey, Manisha
dc.contributor.authorMortensen, Rasmus
dc.contributor.authorCalcutt, Ainslie
dc.contributor.authorPowell, Jessica
dc.contributor.authorBatzloff, Michael R
dc.contributor.authorDietrich, Jes
dc.contributor.authorGood, Michael F
dc.date.accessioned2018-06-15T07:31:10Z
dc.date.available2018-06-15T07:31:10Z
dc.date.issued2016
dc.identifier.issn0022-1767
dc.identifier.doi10.4049/jimmunol.1501994
dc.identifier.urihttp://hdl.handle.net/10072/100159
dc.description.abstractCluster of virulence responder/sensor (CovR/S) mutant group A streptococci (GAS) are serious human pathogens of multiple M protein strains that upregulate expression of virulence factors, including the IL-8 protease Streptococcus pyogenes cell envelope proteinase (SpyCEP), thus blunting neutrophil-mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. We previously showed that a combination vaccine incorporating J8-DT (conserved peptide vaccine from the M protein) and a recombinant SpyCEP fragment protects against CovR/S mutants. To enhance the vaccine’s safety profile, we identified a minimal epitope (S2) that was the target for anti-SpyCEP Abs that could protect IL-8 from SpyCEP-mediated proteolysis. Abs from healthy humans and from mice experimentally infected with GAS also recognized S2, albeit at low titers. Native SpyCEP may be poorly immunogenic (cryptic or subdominant), and it would be to the organism’s advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2) that protect IL-8 from proteolysis and other Abs (anti-J8) that cause strain-independent killing in the presence of neutrophils. We show that either component alone is ineffectual in preventing skin infection and bacteremia due to CovR/S mutants but that the combination induces complete protection. This protection correlated with a significant influx of neutrophils to the infection site. The data strongly suggest that the lack of natural immunity to hypervirulent GAS strains in humans could be rectified by this combination vaccine.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association of Immunologists
dc.relation.ispartofpagefrom3364
dc.relation.ispartofpageto3374
dc.relation.ispartofissue8
dc.relation.ispartofjournalJournal of Immunology
dc.relation.ispartofvolume196
dc.subject.fieldofresearchImmunology
dc.subject.fieldofresearchImmunology not elsewhere classified
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchcode3204
dc.subject.fieldofresearchcode320499
dc.subject.fieldofresearchcode3101
dc.titleCombinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyOffice of the Snr Dep Vice Chancellor, Institute for Glycomics
gro.rights.copyrightSelf-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
gro.hasfulltextNo Full Text
gro.griffith.authorPandey, Manisha
gro.griffith.authorGood, Michael F.


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