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Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice
Ronan K. Carroll, … , Anthony R. Flores, James M. Musser
Ronan K. Carroll, … , Anthony R. Flores, James M. Musser
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1956-1968. https://doi.org/10.1172/JCI45169.
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Research Article Infectious disease Article has an altmetric score of 1

Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice

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Abstract

Infection with different strains of the same species of bacteria often results in vastly different clinical outcomes. Despite extensive investigation, the genetic basis of microbial strain-specific virulence remains poorly understood. Recent whole-genome sequencing has revealed that SNPs are the most prevalent form of genetic diversity among different strains of the same species of bacteria. For invasive serotype M3 group A streptococci (GAS) strains, the gene encoding regulator of proteinase B (RopB) has the highest frequency of SNPs. Here, we have determined that ropB polymorphisms alter RopB function and modulate GAS host-pathogen interactions. Sequencing of ropB in 171 invasive serotype M3 GAS strains identified 19 distinct ropB alleles. Inactivation of the ropB gene in strains producing distinct RopB variants had dramatically divergent effects on GAS global gene expression. Additionally, generation of isoallelic GAS strains differing only by a single amino acid in RopB confirmed that variant proteins affected transcript levels of the gene encoding streptococcal proteinase B, a major RopB-regulated virulence factor. Comparison of parental, RopB-inactivated, and RopB isoallelic strains in mouse infection models demonstrated that ropB polymorphisms influence GAS virulence and disease manifestations. These data detail a paradigm in which unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections.

Authors

Ronan K. Carroll, Samuel A. Shelburne III, Randall J. Olsen, Bryce Suber, Pranoti Sahasrabhojane, Muthiah Kumaraswami, Stephen B. Beres, Patrick R. Shea, Anthony R. Flores, James M. Musser

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Figure 4

Group A streptococcal strains with RopB single-amino-acid replacements produce different amounts of functional SpeB.

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Group A streptococcal strains with RopB single-amino-acid replacements p...
(A and B) The quantity and activity of SpeB produced by strains with each of the RopB variants, analyzed by Western immunoblot (A) and SpeB zymogen (SpeBz) cleavage assay (B). MGAS strain numbers and variations in the RopB sequence are indicated for each sample. As shown in B, the SpeB present in culture supernatants of the wild-type RopB, V7I, and C85Y strains readily processed purified recombinant SpeBz C192S from the 40-kDa form to the 28-kDa form, indicating that the detected SpeB was enzymatically active (36). No SpeB or SpeB activity was detected in supernatants from the other strains. Strain MGAS315ΔspeB and sterile THY broth were used as negative controls. In both panels, all samples were run simultaneously on multiple gels and, following image acquisition, lanes were reordered such that RopB polymorphisms were ordered left to right with respect to the amino acid sequence.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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