Document Detail


Complement-mediated opsonization of invasive group A Streptococcus pyogenes strain AP53 is regulated by the bacterial two-component cluster of virulence responder/sensor (CovRS) system.
MedLine Citation:
PMID:  23928307     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Group A Streptococcus pyogenes (GAS) strain AP53 is a primary isolate from a patient with necrotizing fasciitis. These AP53 cells contain an inactivating mutation in the sensor component of the cluster of virulence (cov) responder (R)/sensor (S) two-component gene regulatory system (covRS), which enhances the virulence of the primary strain, AP53/covR(+)S(-). However, specific mechanisms by which the covRS system regulates the survival of GAS in humans are incomplete. Here, we show a key role for covRS in the regulation of opsonophagocytosis of AP53 by human neutrophils. AP53/covR(+)S(-) cells displayed potent binding of host complement inhibitors of C3 convertase, viz. Factor H (FH) and C4-binding protein (C4BP), which concomitantly led to minimal C3b deposition on AP53 cells, further showing that these plasma protein inhibitors are active on GAS cells. This resulted in weak killing of the bacteria by human neutrophils and a corresponding high death rate of mice after injection of these cells. After targeted allelic alteration of covS(-) to wild-type covS (covS(+)), a dramatic loss of FH and C4BP binding to the AP53/covR(+)S(+) cells was observed. This resulted in elevated C3b deposition on AP53/covR(+)S(+) cells, a high level of opsonophagocytosis by human neutrophils, and a very low death rate of mice infected with AP53/covR(+)S(+). We show that covRS is a critical transcriptional regulator of genes directing AP53 killing by neutrophils and regulates the levels of the receptors for FH and C4BP, which we identify as the products of the fba and enn genes, respectively.
Authors:
Garima Agrahari; Zhong Liang; Jeffrey A Mayfield; Rashna D Balsara; Victoria A Ploplis; Francis J Castellino
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural     Date:  2013-08-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-23     Completed Date:  2013-11-26     Revised Date:  2014-09-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  27494-504     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bacterial Proteins / biosynthesis,  genetics,  metabolism*
Carrier Proteins / biosynthesis,  genetics
Complement C3b / genetics,  metabolism
Complement C4b-Binding Protein / genetics,  metabolism
Complement Factor H / genetics,  metabolism
Female
Humans
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Male
Mice
Neutrophils / metabolism*,  microbiology,  pathology
Phagocytosis*
Protein Binding
Repressor Proteins / genetics,  metabolism*
Streptococcal Infections / genetics,  metabolism,  pathology
Streptococcus pyogenes / genetics,  metabolism,  pathogenicity*
Virulence Factors / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
HL013423/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Bacterial Proteins; 0/C4BPA protein, human; 0/Carrier Proteins; 0/Complement C4b-Binding Protein; 0/CovS protein, Streptococcus pyogenes; 0/CsrR protein, Streptococcus pyogenes; 0/Enn protein, Streptococcus pyogenes; 0/Fba protein, Streptococcus pyogenes; 0/Intracellular Signaling Peptides and Proteins; 0/Repressor Proteins; 0/Virulence Factors; 80295-43-8/Complement C3b; 80295-65-4/Complement Factor H
Comments/Corrections

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